RFA-HL-01-004: BLOOD AND MARROW TRANSPLANT CLINICAL RESEARCH NETWORK

BLOOD AND MARROW TRANSPLANT CLINICAL RESEARCH NETWORK

Release Date: January 4, 2001

RFA: RFA-HL-01-004 (Limited competition request for competing applications, see NOT-HL-05-119)

National Heart, Lung, and Blood Institute
(http://www.nhlbi.nih.gov/index.htm)
National Cancer Institute
(http://www.nci.nih.gov/)

Letter of Intent Receipt Date: February 21, 2001
Application Receipt Date: March 19, 2001

PURPOSE

The National Heart, Lung, and Blood Institute and the National Cancer
Institute invite applications to participate in a Blood and Marrow Transplant
Clinical Research Network (Network) of interactive clinical research groups.
This network will promote the efficient comparison of novel treatment methods
and management strategies of potential benefit for children and adults
undergoing blood or marrow transplantation. The objective of these Requests
for Applications (RFAs) is to establish and maintain (1) the infrastructure
required for a network of up to twenty core clinical centers to perform
multiple clinical trials for persons undergoing a hematopoietic stem cell
transplant and (2) a Data Coordinating Center for the network. The project
period for the Blood and Marrow Transplant Clinical Research Network will be
five years. There will be an administrative review after approximately three
years to determine if the network has been performing important comparative
studies as envisioned. If so, the announcement of a competitive renewal for
an additional five years is anticipated. Thus the network is expected to be
funded for a maximum of ten years.

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, "Blood and
Marrow Transplant Clinical Research Network," is related to the priority
areas of chronic disabling conditions, cancer, and clinical prevention
services. Potential applicants may obtain a copy of “Healthy People 2010"
at http://www.health.gov/healthypeople/.

ELIGIBILITY REQUIREMENTS

Applications may be submitted from organizations located in the United States
of America. This geographic constraint is necessary because of the need for
close communication among members of the program, the requirement for
frequent steering committee meetings, and the necessity of site visits for
data verification. 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
may apply.

The disciplines and expertise that will be sought for this program include
but are not limited to the areas of pediatrics, infectious disease, internal
medicine, hematology, oncology, immunology, pharmacology, therapeutic
development, biostatistics and clinical trials management. Racial/ethnic
minority individuals, women, and persons with disabilities are encouraged to
apply as Principal Investigators. All current policies and requirements that
govern the research programs of the National Institutes of Health (NIH) will
apply to grants awarded under this RFA.

Awards for a Core Clinical Center and a Data Coordinating Center under this
RFA will not be made to the same Principal Investigator to ensure that data
analysis is conducted independently of data acquisition. The same
institution may apply for both a Core Clinical Center and the Data
Coordinating Center award, but the applications for each must be from
different individuals.

MECHANISM OF SUPPORT

This RFA will use the cooperative agreement (U01) administrative and funding
mechanism of support. Under the cooperative agreement, the NIH assists,
supports, and/or stimulates, and is substantially involved with recipients in
conducting a study by facilitating performance of the effort in a "partner"
role. Details of the responsibilities, relationships, and governance of a
study funded under a cooperative agreement are discussed later in this
document.

The project period for applications submitted in response to this RFA will be
five years. An administrative review will be conducted in approximately the
third year of the network to determine whether or not the network program
should be announced for another five-year funding period. The total project
period for this program will be no longer than 10 years.

The anticipated award date is September 30, 2001. Awards for Core Clinical
Centers are limited to $405,000 total costs per year. (Total costs include
Facility & Administrative costs, also called indirect costs or overhead.)
This includes up to $150,000 total costs to support core activities and up to
$255,000 total costs for per-patient costs. The award for the Data
Coordinating Center will comprise total costs per year for routine data
center functions. In addition to a well documented budget for data
coordinating activities, Data Coordinating Center applicants should request a
line item of additional funds of $500,000 total costs per year specifically
for biologic reagents, centralized laboratory costs and enrollment of
additional patients or those from non-Core centers.

FUNDS AVAILABLE

An estimated sixteen awards for Core Clinical Centers and one award for a
Data Coordinating Center will be made under this RFA. A maximum of $40
million (total costs) over a five-year period will be awarded. Because the
nature and scope of the research proposed in response to this RFA may vary,
it is anticipated that the size of an award may also vary in all years.
Funds for patient-related costs will be restricted and released concordant
with patient enrollment. Future year costs will be distributed based on the
recommended protocols.

Although the financial plans of NHLBI and NCI provide support for this
program at levels of $6 million and $2 million per year, respectively, awards
pursuant to this RFA are contingent upon the availability of funds and the
receipt of a sufficient number of meritorious applications. Designated
funding levels are subject to change at any time prior to final award, due to
unforeseen budgetary, administrative, or scientific developments.
RESEARCH OBJECTIVES

Background

Several new developments in the field of allogeneic hematopoietic stem cell
transplantation have substantially decreased transplant-related morbidity and
promise to make major improvements in both the safety and efficacy of
transplantation, allowing transplantation to be extended to more patients.
Use of matched unrelated marrow donors, unrelated cord blood units, and
partially matched family donors have greatly expanded the options for
patients who lack an HLA identical sibling donor. Use of stem cells mobilized
and collected from peripheral blood rather than harvested from bone marrow
speeds engraftment and may improve treatment outcome. Manipulation of the
transplant to adjust the dose of stem cells and lymphocytes to optimum
numbers (graft engineering) may also be beneficial. The use of non-
myeloablative transplants (mini-transplants) promises to extend the safe
application of stem cell allografts to individuals over 60 years and to
patients with non-lethal hematologic diseases. Recently identified human
minor histocompatibility antigens may provide another variable for predicting
the severity of graft-versus-host disease.

There is an urgent need to evaluate these promising new therapeutic
approaches to hematopoietic stem cell transplantation and to disseminate the
findings to health care professionals, patients and the public. Each year,
thousands of patients undergo hematopoietic stem cell transplants in the
United States, yet few of these patients are offered the option to enroll in
a research protocol to study and improve the outcome of this life-saving but
toxic and expensive procedure. There are several reasons why a blood and
marrow transplant clinical research network would accelerate clinical
research and evaluate new approaches to transplantation. The heterogeneity
of hematopoietic stem cell transplant patients makes it difficult to
accumulate a large number of comparable patients in one center. Multi-center
trials will reduce the number of patients needed at each clinical center and
allow accrual to be completed more rapidly. Further, a common treatment
protocol will reduce variables that contribute to patient outcome and allow
valid comparisons between treatments. Finally, the Network approach will
increase the number of comparative trials that are conducted by providing a
framework for rapid initiation of important studies, a focus on randomized
studies, and efficient use of pooled clinical expertise and data management
resources.

Organization of the Blood and Marrow Transplant Clinical Research Network

The Blood and Marrow Transplant Clinical Research Network (Network) will be a
cooperative network of sixteen Core Clinical Centers, one Data Coordinating
Center, the National Heart, Lung, and Blood Institute (NHLBI) and the
National Cancer Institute (NCI). Core Clinical Centers will be responsible
for proposing protocols that could be adopted by the Network, guiding
protocol development, enrolling patients, analyzing results, and
disseminating research findings. All Core Clinical Centers will be required
to participate in a cooperative and interactive manner with one another and
with the Data Coordinating Center. Transplant centers have the option to form
a consortium and apply as a single entity for a Core Clinical Center award.
In the case of a consortium, there will be one Principal Investigator who
will serve on the Steering Committee and represent the other centers, and the
maximum total costs per year will be limited to $405,000.

A centralized Data Coordinating Center will support the activities of the
Network. These include developing protocols, devising novel comparative
study designs, providing sample size calculations and statistical advice,
developing data forms, performing data analyses, coordinating the activities
of the Steering Committee, Protocol Review Committee, and Data and Safety
Monitoring Board, and overall study coordination and quality assurance. In
addition, in order to hasten accrual in phase III protocols, the Coordinating
Center with NHLBI and NCI and the Steering Committee will have the
responsibility to identify qualified and interested investigators at non-Core
centers who wish to enroll patients on these protocols. Arrangements for
data collection and reimbursement of trial-related data collection costs at
non-Core centers will be the responsibility of the Data Coordinating Center.
The Data Coordinating Center will also be responsible for obtaining biologic
reagents, organizing correlative laboratory studies, arranging for storage of
patient samples, and procuring other resources as required by the clinical
protocols.

A Steering Committee will be the main governing body of the Network and, at a
minimum, will be composed of the principal investigators of the Core Clinical
Centers and the Data Coordinating Center and the NHLBI and NCI Project
Scientists. The Steering Committee Chairperson, who will be someone other
than an NHLBI or NCI staff member and may be someone other than a principal
investigator, will be selected by NHLBI and NCI. The Core Clinical Centers,
the Data Coordinating Center, NHLBI and NCI each will have one vote. The
(Chairperson) will vote in the case of ties. The Steering Committee may meet
as often as three to six times in the first 12 months of the Network, and two
to four times per year thereafter. All major scientific decisions will be
determined by majority vote of the Steering Committee.

The Steering Committee will have primary responsibility for the general
organization of the Network, finalizing common clinical protocols,
facilitating the conduct and monitoring of the studies, and reporting study
results. Topics for the protocols will be proposed and prioritized by the
Steering Committee with input from the wider transplant community. For each
protocol, one investigator (or small group) will take the lead responsibility
for drafting the protocol along with the Data Coordinating Center, although
the Steering Committee will provide input and will be responsible for
assuring development of a common protocol to be implemented by other Clinical
Centers.

Subcommittees of the Steering Committee will be established as necessary; for
example, it is envisioned that a Publications and Presentations Committee
will prioritize, facilitate and supervise preparation and review of
manuscripts prior to submission for publication. Subcommittees to oversee
reporting of graft versus host disease and establishment of an infectious
diseases registry are also envisioned. Data collections will be monitored in
a manner consistent with Guidelines for Data Quality Assurance in Clinical
trials and Observational Studies
http://www.nhlbi.nih.gov/funding/policies/dataqual.htm.

An independent Protocol Review Committee, established by NHLBI and NCI with
input from the Steering Committee, will provide peer review for each
protocol. A Data and Safety Monitoring Board (DSMB), similarly established,
will monitor patient safety and review performance of each study
approximately semi-annually. As a part of its monitoring responsibility, the
DSMB will submit recommendations to NHLBI and NCI regarding the continuation
of each study and prepare a report for principal investigators to provide to
their institutional review boards (IRBs.)

It is anticipated that each protocol will be implemented in at least two or
more of the Core Clinical Centers. As specific protocols are developed,
support will depend on the availability of funds and will be provided on a
per patient basis. All the Core Clinical Centers must be willing to pursue
this funding arrangement for each new protocol conducted. Clinical protocols
must be approved by local IRBs and the Protocol Review Committee before
initiation. The exact number of protocols supported in the 5 year program
will depend on the nature and extent of the investigations proposed by the
Steering Committee. Both short and long term projects should be considered.

Research Scope

The objective of this RFA is to establish a Network that will accelerate
research in hematopoietic stem cell transplantation by comparing novel
therapies to existing ones. Therapeutic trials may involve investigational
drugs, drugs already approved but not currently used, and drugs currently
used. The NIH encourages randomization; non-randomized trials will be
supported in exceptional cases only. Randomization may be between different
doses/graft compositions/modes of novel treatment or novel treatment versus
standard therapy. Proposed studies must be ready for multi-center testing.

Some examples of research questions appropriate for this RFA include, but are
not limited to the following:

Trial of sources of stem cells (cord blood transplants versus marrow, and/or
versus mPBSC; mismatched family or unrelated donor).

Trial of graft engineering (making a graft of specific subsets of cells like
stem cells, T cells, and natural killer cells) versus a standard transplant.

Trial of ex vivo expansion of stem cells (from peripheral blood or cord
blood) versus conventional transplants, or comparing different methods of
expansion, or mixed cord blood units.

Trial of mini-transplants (has a less toxic conditioning regimen; relies on
donor cells to stabilize engraftment) in older patients or with diseases
where a toxic conditioning regimen is not needed such as sickle cell disease,
thalassemia or Fanconi anemia versus a conventional transplant.

Trial of conditioning regimens or other aspects of preparative or supportive
therapy versus standard of care.

Trial of red cell or platelet growth factors versus none to improve
engraftment and survival.

Trial of new immunosuppressive drugs, monoclonal antibodies, or cytokines
versus standard of care immunosuppression.

Trial of IL-11 in stimulating engraftment and preventing disease recurrence.

Trial of IL-7 in preventing post transplant infections and relationship to
GvHD.

Trial of donor leukocyte infusions prophylactically versus as treatment for
relapse, infections, or secondary malignancies.

Trial of virus-specific ex vivo activated T cells versus standard therapy.

Trial of general versus specific immunomodulation.

Patient management trial: hematopoietic stem cell transplant versus
chemotherapy for acute leukemia.*

Patient management trial: effect of prior interferon or STI-571 therapy on
the outcome of hematopoietic stem cell transplantation for chronic
myelogenous leukemia.*

Patient management trial: trial of stem cell transplants in patients with
autoimmune disease versus high dose chemotherapy alone.*

Patient management trial: trial of hematopoietic stem cell transplant versus
conventional treatment for sickle cell disease.*

* All patient management trials must be accompanied by a letter of
collaboration from the chief of the clinical division responsible for
referring the patients, for example oncology, rheumatology, or hematology.
In addition, the Network will conduct patient management trials in
collaboration with other groups that have an interest in the subject patient
population, for example the cancer cooperative groups.

These are examples only. Applicants are not limited to the subjects
mentioned above and are encouraged to submit other topics pertinent to the
objectives of the RFA.

Research Plan

Core Clinical Center applicants should propose a research plan that includes
one protocol as a model for the network. The protocol should be short term
and capable of completion within 18 to 36 months. Priority will be given to
randomized studies. The protocols should demonstrate knowledge in the field
of hematopoietic stem cell transplantation, ask clinically relevant
questions, and require sufficient subjects to necessitate the use of a multi-
center network. Applicants should provide preliminary results that justify
the proposed end points and sample size.

The research plan should follow the instructions in the PHS 398 application
form which can be found at http://grants.nih.gov/grants/forms.htm. For the
protocol, include a two to three page description of the rationale, research
aims, outcome measures, and study design; a description of the patient
populations with an estimate of the expected distribution of male and female
patients, ages, and assurances of the applicant's access to the patient
populations. Identify any competing protocols and provide an algorithm to
explain patient allocation among them.

Core Clinical Center applicants should indicate for each protocol how many
patients are available in the applicant’s center and how many will be
required from the network. The center’s estimate of eligible patients should
be based on the actual number of transplants performed in the year 2000.
Please complete the following table by providing the number of patients
transplanted at your institution in the year 2000 in each category.

Transplants
in 2000 - Related - Mismatched Related - Unrelated - Autologous
-----------------------------------------------------------------------------
Marrow - - - -
-----------------------------------------------------------------------------
mPBSC - - - -
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Cord Blood - - - -
-----------------------------------------------------------------------------
Pediatric - - - -
-----------------------------------------------------------------------------
Adult - - - -
-----------------------------------------------------------------------------
Malignant - - - -
-----------------------------------------------------------------------------
Non-malignant - - - -
-----------------------------------------------------------------------------
On protocol - - - -
-----------------------------------------------------------------------------
Randomized - - - -
-----------------------------------------------------------------------------
Multi Center - - - -
-----------------------------------------------------------------------------

It is the intent of this network that multiple trials will be conducted
during the five year project period. It is anticipated that in the initial
year, two trials will be selected from the studies proposed by the successful
applicants. However, a decision to fund a particular Core Clinical Center
will not commit the Network to develop that center’s clinical protocol.
Nevertheless, awardees must agree to actively enroll patients in at least two
Network trials. Applicants should plan that after the first year at least
three trials will begin enrolling patients each year. All applicants should
propose a strategy to streamline protocol development and acceptance among
centers, given this ambitious pace for initiating trials. Initiation of
trials in future years will depend on satisfactory progress in previous
trials.

Data Coordinating Center applicants should propose one clinical protocol from
the perspective of study design, implementation, coordination and data
analysis. Include a plan for recruiting patients from non-Core centers for
studies that warrant it. Indicate appropriate objective measures of primary
and secondary outcome. Describe methods to standardize reporting of graft
versus host disease, propose a registry to track serious infectious
complications, show plans to undertake quality of life studies and present an
innovative approach for performing randomized studies at an early stage of
investigation. Such approaches include, but are not limited to, use of
internal pilot studies, methods for early stopping for futility or benefit,
methods of adaptive trial redesign and other recently developed methods which
will increase the efficiency of trial conduct. Development of new methods is
encouraged.

The entire application for Core Clinical Centers including protocols should
not exceed the Form 398 Research Plan instructions of 25 pages. The Data
Coordinating Center application may include an additional 5 pages to
accommodate the clinical protocol proposal.

SPECIAL REQUIREMENTS

Terms and Conditions of Award

The cooperative agreement is an award instrument establishing an "assistance"
relationship (in contrast to an "acquisition" relationship) between NHLBI,
NCI and a recipient, in which substantial NHLBI and NCI scientific and/or
programmatic involvement with the recipient is anticipated during performance
of the activity. The NHLBI and NCI purpose is to support and/or stimulate
the recipient's activity by involvement in and otherwise facilitating the
activity in a "partner" role, but avoiding a dominant role, direction, or
prime responsibility. The terms and conditions below elaborate on these
actions and responsibilities, and the awardee agrees to work with the NHLBI
and NCI Project Scientists toward achieving the project objectives. It is
anticipated that these terms and conditions will enhance the relationship
between the NHLBI and NCI staff and the principal investigator(s), and will
facilitate the successful conduct and completion of the study. 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
part 74, and other HHS, PHS, and NIH grant administrative policy statements.
The terms will be as follows:

A. Awardee Rights and Responsibilities

A centralized Data Coordinating Center will support the activities of the
Network. These include developing protocols, devising novel comparative
study designs, providing sample size calculations and statistical advice,
developing data forms, performing data analyses, coordinating the activities
of the Steering Committee, Protocol Review Committee, and Data and Safety
Monitoring Board, and overall study coordination and quality assurance. In
addition, in order to hasten accrual in phase III protocols, the Coordinating
Center with NHLBI and the Steering Committee will have the responsibility to
identify qualified and interested investigators at non-Core centers who wish
to enroll patients on these protocols. Arrangements for data collection and
reimbursement of trial-related data collection costs at non-Core centers will
be the responsibility of the Data Coordinating Center. The Data Coordinating
Center will also be responsible for obtaining biologic reagents, organizing
correlative laboratory studies, arranging for storage of patient samples, and
procuring other resources as required by the clinical protocols.

1. Development of Network Research Agenda and Protocols

It is the responsibility of the awardee(s) to develop the details of the
research design, including definition of objectives and approaches, the
planning, implementation, and analysis of studies, any modification of study
design, quality control, collaboration with other investigators, and the
publication of results, interpretations, and conclusions of studies, unless
otherwise provided for in these terms or by action of the Steering Committee.
Modifications and ancillary protocols will be approved by the Data and Safety
Monitoring Board. Ancillary studies will not be funded by this grant
mechanism.

2. Coordination and Internal Oversight of Network Activities

Awardee(s) agree to the governance of the study through a Steering Committee.
Meetings of the Steering Committee will ordinarily be held in the Washington,
D.C. metropolitan area or by telephone conference call. Funds should be
requested for the Chair of the Steering Committee as part of the Data
Coordinating Center budget.

The Steering Committee, with the assistance of the Data Coordinating Center,
is responsible for coordinating protocol development, protocol submission,
study conduct, quality control and study monitoring, drug ordering, data
management, statistical analysis, protocol amendments/status changes,
adherence to requirements regarding investigational drug management and
federally mandated regulations, and protocol and performance reporting. The
Data Coordinating Center will be responsible for communication with the
appropriate NHLBI and NCI staff.

The Steering Committee Chairperson, who will be someone other than an NHLBI
or NCI staff member and may be someone other than a principal investigator,
will be selected by NHLBI and NCI. The Core Clinical Centers, the Data
Coordinating Center, NHLBI and NCI each will have one vote. The
(Chairperson) will vote in the case of ties. The Steering Committee may meet
as often as three to six times in the first 12 months of the Network, and two
to four times per year thereafter. All major scientific decisions will be
determined by majority vote of the Steering Committee.

3. Protocol Submission and Approval

A protocol is the detailed written plan of a clinical experiment. Formal
protocol review and NHLBI and NCI approval prior to activation are required.
A Protocol Review Committee (PRC), independent from study investigators and
appointed by the Directors, NHLBI and NCI, will meet at regular intervals to
review proposed protocols. The Steering Committee may recommend members for
the PRC. Meetings will ordinarily be held in the Washington, D.C.
metropolitan area. The NHLBI or NCI Project Scientist shall serve as
Executive Secretary for the PRC. The Executive Secretary will provide the
study chairman with the Protocol Review Committee's consensus review that
describes recommended modifications and other suggestions, as appropriate.
Every effort should be made to expedite the protocol approval process.

Protocols should adhere to recent NIH polices including inclusion of
women/minorities, children,
http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm and
http://grants.nih.gov/grants/funding/children/children.htm and
http://orwh.od.nih.gov/pubs/outreach.pdf. The data monitoring plan should
also be consistent with recent guidelines
http://www.nhlbi.nih.gov/funding/policies/dataqual.htm as should the plans
for analysis for gender/minority for NIH defined Phase III trials.

The major considerations relevant to protocol review by the PRC include: (a)
the strength of the scientific rationale supporting the study, (b) the
medical importance of the question being posed, (c) the avoidance of
undesirable duplication with other ongoing studies, (d) the appropriateness
of study design including interim monitoring plans if appropriate, (e) a
satisfactory projected accrual rate and follow-up period, (f) patient safety,
(g) compliance with federal regulatory requirements, (h) adequacy of data
management, (i) appropriateness of patient selection, evaluation, assessment
of toxicity, response to therapy and follow-up, (j) adherence to NIH
guidelines as detailed above.

4. Network Compliance with Federally Mandated Regulatory Requirements

The Network must comply with all FDA regulatory requirements for studies
involving investigational devices and agents and NIH policies applying to the
conduct of research involving human subjects and be consistent with Office of
Human Research Protections guidelines http://www.hhs.gov/ohrp/.
These regulations include but are not limited to CFR 21 Parts 50, 56 and
312 and CFR 45 Part 46. Awardees are required to follow established Network
procedures for complying with the federally mandated regulations. Each
awardee must:

a. have a current approved multiple project assurance number on file with
OHRP or obtain a single project assurance;

b. have IRB approval for each protocol, amendment, and informed consent
document prior to patient entry and at least annually thereafter, as
appropriate for the degree of risk of the protocol, as stipulated by 45 CFR
46;

c. provide the Data Coordinating Center with a current FDA Form 1572 and
curriculum vitae for study investigators;

d. provide evidence that each patient (or legal representative) has given
written informed consent prior to entry on study;

e. assure timely reporting of all serious and unexpected toxicities to the
Data Coordinating Center, who will report them to NHLBI, NCI and other
parties as appropriate;

f. establish and maintain an on-site audit program according to Network
procedures; and

g. comply with all FDA monitoring and reporting requirements for
investigational agents and devices.

h. Data Collection and Management

The Network shall establish and implement mechanisms for data collection and
management that are: (a) adequate for quality control and analysis, and (b)
as simple as possible in order to encourage maximum participation of
physicians entering patients and to avoid unnecessary expenses. Awardees are
required to follow Network procedures for data collection and management
which will be developed by the Steering Committee.

6. Quality Control and Monitoring of Therapeutic and Diagnostic Modalities

The Steering Committee shall establish and implement mechanisms for quality
control of therapeutic and diagnostic modalities employed in its trials.
Awardees are required to follow Network procedures for quality control.
Quality control should include an initial determination of patient
eligibility by the Data Coordinating Center prior to study enrollment. In
addition, quality control procedures should include at a minimum concurrent
or retrospective review to assure compliance with the protocol for radiation
therapy, and consistency of evaluation of graft versus host disease,
infectious disease reporting, determination of relapse versus graft failure,
and other key endpoints.

7. Study Monitoring and Quality Assurance

The Network shall establish and implement mechanisms for study monitoring and
quality assurance. Awardees are required to follow Network procedures for
study monitoring. The Network is responsible for assuring accurate and
timely knowledge of the progress of each study through:

a. tracking and reporting of patient accrual and adherence to defined accrual
goals;

b. ongoing assessment of case eligibility and availability;

c. timely medical review and assessment of patient data;

d. rapid reporting of treatment-related morbidity and measures to ensure
communication of this information to all parties;

e. interim evaluation and consideration of measures of outcome as consistent
with patient safety and good clinical trials practice;

f. timely communication of results of studies; and

g. an on-site monitoring program.

The NHLBI/NCI is responsible for ensuring that all participating sites
receive routine audits by the Data Co-ordinating Center. In the event that
an awardee fails to comply with these guidelines, the accrual of new patients
to the Network's protocols at the affected site shall be suspended
immediately upon notice of the determination. The suspension will remain in
effect until the awardee conducts the required audit and the audit report or
remedial action is accepted by the NHLBI and NCI. The Data Coordinating
Center and NHLBI/NCI will be responsible for notifying any affected site of
the suspension. During the suspension period, no funds from this award may
be provided to the site for new accruals, and no charges to the award for new
accruals will be permitted.

8. Performance Review of Participating Centers

The Network shall establish and follow policies and procedures for
credentialing participating institutions and conducting periodic review of
the performance of each participating site. This review should examine
patient accrual, data accuracy and timeliness, protocol compliance, long-term
patient follow-up and audit results. NHLBI/NCI will make adjustments in
center budgets based on accrual and performance.

9. Quality Assurance and Quality Control of Data Management.

The Data Coordinating Center must follow procedures developed by the Network
for quality assurance and quality control of data collected by the Network
and for the prevention and/or identification of false or otherwise unreliable
data. These procedures must be approved by NHLBI and NCI. If there is any
indication through the quality assurance and/or quality control programs, or
through any other means, of a pattern of non-compliance with protocol or
regulatory requirements or a finding of possible alteration of data, these
findings must be reported to NHLBI and NCI.

10. Reporting Requirements

Reporting requirements will be in agreement with Network procedures, NHLBI
and NCI policies, and FDA regulations. Interim reports of each activated and
ongoing study shall appear in the minutes of each Network meeting and shall
include specific data on patient accrual as well as, when appropriate,
detailed reports of treatment-associated morbidity. Monthly accrual and
screening information must be provided by the Data Monitoring Center to the
NHLBI and NCI Project Scientists for all active studies. A system for
providing such information in a timely manner should be in place. Awardees
must provide screening data to the Data Coordinating Center in accordance
with Network procedures. Annual scientific progress reports will be
submitted by each awardee to the NHLBI and NCI. New reporting requirements
should also be implemented
http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm.

11. Data and Safety Monitoring Board (DSMB)

A Data and Safety Monitoring Board will (DSMB) be appointed by the Directors,
NHLBI and NCI to provide overall monitoring of interim data and safety
issues. The Steering Committee may suggest members for the DSMB. There will
be a single DSMB for all studies conducted by the Network. Members who are
lead investigators from institutions enrolling patients in a protocol under
DSMB review will be required to recuse themselves for that review. The DSMB
will meet semi-annually, usually in Bethesda, MD. The NHLBI or NCI Project
Scientist shall serve as Executive Secretary for the DSMB.

12. Adverse Event Procedures

In order to comply with FDA regulations, the awardee must promptly notify the
Data Coordinating Center Principal Investigator or designee, and the NHLBI
and NCI Project Scientists of serious and unexpected adverse events as
instructed in the protocol.

13. Protocol Closure

The Network shall establish and implement mechanisms for interim monitoring
of results and accrual. If the Network wishes to close accrual to a study
prior to meeting the initially established accrual goal, the request should
be referred to the DSMB for review and to NHLBI and NCI for concurrence prior
to implementation of the decision by the Network. It is recommended that
statistical guidelines for early closure be presented as explicitly as
possible in the protocol in order to facilitate these decisions.

14. Industry or Third-party Involvement

Support or other involvement of industry or any other third party in the
study -- e.g., participation by the third party; involvement of project
resources or citing the name of the project or the NHLBI and NCI support; or
special access to project results, data, findings or resources -- may be
advantageous and appropriate. Joint projects and cost-sharing arrangements
with industry are encouraged. Arrangements will be worked out on a
case-by-case basis by the Network leadership and collaborating companies.
Arrangements will in all cases conform to federal regulations and any
applicable NHLBI and NCI policies on interactions among industry, cooperative
trials networks, and NHLBI and NCI. In all cases, details of any financial
or other arrangements between the Network and industrial companies must be
approved by NHLBI and NCI.

15. Release of Study Data

Awardees will retain custody of and have primary rights to the data developed
under these awards, subject to Government rights of access consistent with
current federal policies. The collaborative protocol and governance policies
will require submission of data to the coordinating center for a
collaborative database; specify procedures for data analysis, reporting and
publication; and include procedures to protect and ensure the privacy of
medical and genetic data and records of individuals. Copies of the
collaborative data sets will be provided to each principal investigator after
publication of study results. Each Awardee will comply with the approved data
release plan.

At the end of the project, the Data Coordinating Center is expected to
electronically place all study protocols and procedure manuals in the public
domain and/or make them available to other interested parties at no charge
other than the costs of reproduction and distribution, according to the
approved plan for making data and materials available to the scientific
community.

16. Termination or Curtailment

The NHLBI and NCI reserve the right to terminate or curtail the Network, a
protocol, or an individual award in the event of (a) failure to develop or
implement a mutually agreeable collaborative protocol, (b) substantial
shortfall in participant recruitment, follow-up, data reporting, quality
control, or other major breach of the protocol, (c) substantive changes in
the agreed-upon protocol with which NHLBI and NCI cannot concur, (d) reaching
a major study endpoint substantially before schedule with persuasive
statistical significance, or (e) human subject concerns that may dictate a
premature termination.

17. Procedures in the Event of Scientific Misconduct

It is the responsibility of the grantee institution to notify NHLBI/NCI of
potential conflicts of interest with Network protocols as published in
FINANCIAL CONFLICTS OF INTEREST AND RESEARCH OBJECTIVITY: ISSUES FOR
INVESTIGATORS AND INSTITUTIONAL REVIEW BOARDS
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-040.html.

If a duly authorized governmental or institutional body issues a final
determination that scientific misconduct has occurred or if the awardee
determines that other events have occurred which have significantly affected
the quality or integrity of the Network data or patient safety, the awardee
is responsible for notifying the Network's Data Coordinating Center who will
notify the DSMB, the NHLBI and NCI, the collaborating investigators, and
other sponsors of the affected work. Investigators will notify their IRBs.

The awardee is also responsible, if the events described above have occurred,
for ensuring that submitted but unpublished abstracts and manuscripts are
corrected, if possible. If publication deadlines have passed or if abstracts
and/or manuscripts containing the affected data have already been published,
the awardee is responsible, within 90 days after learning of the event(s)
significantly affecting the quality of the Network data or patient safety,
for submitting to NHLBI and NCI a re-analysis of the results deleting the
false or otherwise unreliable data, and disclosing within the text the
reason(s) for the re-analysis. The awardee must submit the re-analysis for
publication. The NHLBI and NCI may disseminate information about the re-
analysis as broadly as it deems necessary.

The awardee must use its best efforts to notify all scientists, research
laboratories, and other organizations to which the awardee has sent research
materials affected by false or otherwise unreliable data.

True copies of data files and other supporting documentation from studies
affected by scientific misconduct or other findings affecting the quality or
integrity of data or patient safety shall be made available to the NHLBI and
NCI in a timely manner upon the request of the Grants Management Officers,
NHLBI and NCI. The NHLBI and NCI reserve the right to re-analyze, to
publish, or to distribute its analyses of these data when it is in the
interest of the public health. Prior to release, publication or distribution
of such analyses, the NHLBI and NCI will provide such analyses to the
awardee(s).

18. Notification of Patients of Protocol-related Information

In order for there to be an appropriate response in the event the NHLBI and
NCI determine, either while a protocol is active or (if relevant) during the
lifetime of the subjects following protocol closure, that a medically
important toxicity or side effect is associated with protocol-directed
treatment or that the medical care of one or more subjects may have been
compromised by scientific misconduct or other finding affecting the integrity
of the data or patient safety at the awardee institution or at a third-party
institution, funded or unfunded, the awardee shall assure that the
institution(s) responsible for these subject(s') accrual, whether funded or
unfunded, will have procedures in place: a) to contact each subject
individually at his or her last known address on file with the institution
and encourage subjects to notify the institution of any changes of address
and b) which give each subject contacted appropriate information and the
right to communicate with an appropriate institutional representative and, in
the event of misconduct, to meet with a physician not connected with the
clinical trial or study in which the subject has participated. The procedure
must provide for informing the subjects fully of the consequences of the
toxicity or misconduct for their care and well-being, if any, and the
availability of follow-up; and their opportunity to examine any portion of
their medical records relevant to the potential effect of the toxicity or
side effect upon them or that may be affected by scientific misconduct or
other findings affecting the quality or integrity of the data or patient
safety.

Under regulations in CFR 45 Part 74.53, NHLBI and NCI have right of access to
research records pertinent to studies conducted with NHLBI and NCI funding.
In exceptional circumstances, such as a public health emergency, institutions
may be required to provide subject names and treatments to the NHLBI and NCI
in a format which allows direct notification of the patient by the NHLBI and
NCI.

19. There will be an administrative review by NHLBI and NCI after
approximately three years to determine if the network and each of its
components has been performing as envisioned in terms of patient recruitment
and implementation of protocols of importance to the field.

20. All major scientific decisions will be determined by majority vote of the
Steering Committee.

21. Awardees must agree to actively enroll patients in at least two Network
trials.

22. Each clinical center shall be prepared for a yearly audit/site visit by
the Data Coordinating Center.

23. NHLBI/NCI will make adjustments in center budgets based on accrual and
performance.

B. NHLBI and NCI Staff Responsibilities

The role of NHLBI and NCI staff as described throughout these terms and
conditions of award is to assist and facilitate, but not to direct, research
activities. This cooperative agreement is part of a larger program of
cooperative clinical trials in the NHLBI and NCI.

1. NHLBI and NCI Staff Interactions

One NHLBI and one NCI staff member will be members of the Steering Committee.
Because of the Network's diverse research agenda and the number of tasks that
have to be accomplished for the Network to realize its goals, a number of
NHLBI and NCI scientists from several organizational units may also interact
with the Network. These staff scientists may include but are not limited to
individuals with expertise in clinical trial design, recruitment, data
collection, management, and monitoring, biostatistics, use of investigational
agents, knowledge of other relevant ongoing studies, the ability to establish
liaisons with other clinical cooperative groups and those with expertise in
protocol-related and medical matters relating to the diseases under study.

While one NHLBI and one NCI Project Scientist will be members of the Steering
Committee; they or another NHLBI and/or NCI scientist may serve on other
study committees when deemed appropriate by NHLBI and NCI.

NHLBI and NCI staff scientists will review and provide advice regarding
mechanisms established by the Network for quality control of therapeutic and
diagnostic modalities employed in its trials. Staff will review and approve
the mechanisms established by the Network for study monitoring including the
Network's on-site auditing program. Staff may attend the on-site audits
conducted by the Network as observers. The frequency of observer
participation will be determined by the NHLBI and NCI.

NHLBI and NCI staff scientists will review mechanisms established by the
Network for data management. When deemed appropriate, staff will make
recommendations to ensure that data collection and management procedures are:
(a) adequate for quality control and analysis; (b) as simple as appropriate
in order to encourage maximum participation of physicians entering patients
and to avoid unnecessary expense; and (c) generally compatible with the
standard formats for electronic data reporting to NHLBI and NCI. The NHLBI
and NCI will have access to all data although they remain the property of
the awardee institution. Data must also be available for external monitoring
as required by FDA regulations.

2. Involvement in Investigational Drug and Device Management

The NHLBI and NCI have the option to cross file or independently file an IND
on investigational agents evaluated in trials supported under cooperative
agreements. This requirement applies to drugs not developed in the NCI drug
development program. In the case of investigational devices, the NHLBI and
NCI, Network investigators, and the device supplier will decide
collaboratively which organization will hold the IDE. NHLBI and NCI staff
with experience in regulatory affairs or technology transfer must review and
approve agreements regarding investigational agents between the Network and
third-parties.

3. NHLBI and NCI Attendance at Network Meetings

NHLBI and NCI Project Scientists will attend the regular Network Steering
Committee meetings, will serve as the executive secretary for the PRC and
DSMB, and will be invited to Network leadership and subcommittee meetings.

4. Facilitating Collaboration with other Cooperative Groups

NHLBI and NCI Project Scientists will take an active role in promoting the
timely completion of important studies, for example by encouraging and
facilitating intergroup collaboration when appropriate, or by assisting in
the identification and mobilization of additional resources.

C. Arbitration

Any disagreement that may arise in scientific/programmatic matters (within
the scope of the award), between award recipients and the NHLBI and NCI may
be brought to arbitration. An arbitration panel will be composed of three
members--one selected by the Steering Committee (with the NHLBI and NCI
members not voting) or by the individual awardee in the event of an
individual disagreement, a second member selected by NHLBI and NCI, and the
third member selected by the two other members. This panel will review the
area of disagreement and recommend an appropriate course of action to the
Directors, NHLBI and NCI. This special arbitration procedure in no way
affects the awardee's right to appeal an adverse action that is otherwise
appealable in accordance with the federal regulations at 42 CFR part 50,
Subpart D and 45 CFR part 16, or the rights of NHLBI and NCI under applicable
statutes, regulations and terms of the award. The Network will not expend
NHLBI or NCI funds to conduct any study disapproved by NHLBI or NCI unless
the disapproval has been overturned by the arbitration process outlined
above.

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 biomedical and
behavioral research projects involving human subjects, unless a clear and
compelling rationale and justification are 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 research involving human subjects should read the
updated "NIH Guidelines for Inclusion of Women and Minorities as Subjects in
Clinical Research," published in the NIH Guide for Grants and Contracts on
August 2, 2000
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html; a
complete copy of the updated Guidelines are available at
http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm:. The
revisions relate to NIH defined Phase III clinical trials and require: a) all
applications or proposals and/or protocols to 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) all
investigators to report accrual, and to conduct and report 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 the 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 scientific and ethical reasons not to include
them. This policy applies to all initial (Type 1) applications and
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 Awards, March 6, 1998, and is available at the following URL
address: http://grants.nih.gov/grants/guide/notice-files/not98-024.html.
Investigators also may obtain copies of these policies from the program staff
listed under INQUIRIES. Program staff may also provide additional relevant
information concerning the policy.

LETTER OF INTENT

Prospective applicants are asked to submit by February 21, 2001, a letter of
intent that includes a descriptive title of the proposed research, the name,
address, and telephone number of the Principal Investigator, the identities
of other key personnel and participating institutions, 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, the information that it
contains allows NHLBI and NCI staff to estimate the potential review workload
and plan the review.

The letter of intent is to be faxed or mailed to Dr. Deborah Beebe at the
address listed under INQUIRIES.

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 4/98) is to be used in
applying for these grants. These forms are available at most institutional
offices of sponsored research or may be obtained from the Division of
Extramural Outreach and Information Resources, National Institutes of Health,
6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301-435-
0714, E-mail: GrantsInfo@nih.gov. The PHS 398 application kit is also
available on the Internet at http://grants.nih.gov/grants/forms.htm. The
entire application for Core Clinical Centers including protocols should not
exceed the Form 398 Research Plan instructions of 25 pages. The Data
Coordinating Center application may include an additional 5 pages to
accommodate the clinical protocol proposal.

Material to Include in Core Clinical Center Applications:

To promote development of a collaborative program among the award recipients,
the issues discussed below need to be addressed in each application for a
Core Clinical Center and will be considered during the review of the
application. This material is in addition to the submission of a research
plan, as described in the section entitled Research Scope and should be
included within the 25 page limit.

Patient Access. Core Clinical Center applicants must have access to at least
35 patients per year undergoing an allogeneic blood or marrow transplant.
Provide the information requested regarding patient numbers by completing
Table 1. It is not anticipated that all patients will be enrolled in
research protocols at any one time. It is possible that an individual
patient may be enrolled in more than one study. Centers should estimate the
number of patients that will be eligible for Network protocols, provide
information on competing protocols, and present a strategy for allocating
patients between them.

Study population. The application should include a description of the pool
of potential study participants--the age range, ethnic/racial distribution,
estimated distribution of patients with different diseases and type of
transplant. The Network should include as patients racial/ethnic minorities,
children and women in ratios that at least approximate the incidence of the
diseases being studied and provide sufficient clinical events to perform
subgroup analyses.

Patient-related costs. Specific laboratory tests specifically required by
clinical protocols will be included as a part of the per patient costs of
each Core Clinical Center. (Costs for tests that are a routine part of
patients’ clinical care should not be included and may not be paid from grant
funds.)

Plans to release data. Awardees will retain custody of and have primary
rights to the data developed under these awards, subject to Government rights
of access consistent with current federal policies. The collaborative
protocol and governance policies will require submission of data to the
coordinating center for a collaborative database; specify procedures for data
analysis, reporting and publication; and include procedures to protect and
ensure the privacy of medical and genetic data and records of individuals.
Copies of the collaborative data sets will be provided to each principal
investigator after publication of study results. Each Awardee will comply
with the approved data release plan.

Awardees are encouraged to publish and to publicly release and disseminate
results, data and other products of the study, concordant with the study
protocol and governance and the approved plan for making data and materials
available to the scientific community, NHLBI and NCI. No later than three
years beyond the end date of the project period, unpublished data, data sets
not previously released, or other study materials or products are to be made
available to any interested party at no charge other than the costs of
reproduction and distribution. At the end of the project, the Data
Coordinating Center is expected to electronically place all study protocols
and procedure manuals in the public domain and/or make them available to
other interested parties at no charge other than the costs of reproduction
and distribution, according to the approved plan for making data and
materials available to the scientific community.

Willingness to participate in the Network. Applicants should state their
general support of collaborative research and interaction with other Core
Clinical Centers, the Data Coordinating Center, NHLBI and NCI through the
network. Centers must be willing to initiate randomized studies of promising
therapy as soon as it is warranted. Centers must state their willingness to
participate in Network trials even if the protocols they proposed are not
selected for implementation. Applicants should discuss their willingness to
accept per patient reimbursement (capitation) for each protocol as decided by
the Steering Committee.

Budget and Related Issues for Core Clinical Centers

Core Clinical Center applicants should consider the following additional
issues regarding budgets. The underlying concept of the Network is that a
core effort is essential to maintain the infrastructure required to perform
prospective multi-institution clinical trials. Based on this approach, it is
estimated that the Core Clinical Centers will require a minimum level of
effort to sustain the organizational aspects of the Network.

In addition to the core budget, each Core Clinical Center will be provided
funds for implementation of protocols on a per patient-enrolled basis. Funds
for per patient costs will be restricted for this purpose. Costs for a
required part of the patient’s treatment may not be requested from the grant.
Costs for tests and treatment not part of the usual procedure may be
requested. Allowable total costs for each clinical center (core costs, costs
per patient to conduct the protocols, and facility and administrative costs)
will be limited to $405,000 a year.

The precise number of protocols conducted over the 5 years will be determined
by the Network Steering Committee and will depend on availability of funds.
Each clinical center must participate in at least two protocols per year.
The initiation of two protocols is expected in the first year, and at least
four new trials are expected to begin enrolling patients in future years.
Initiation of trials in future years will depend on satisfactory progress in
previous trials.

Applicants for the Core Clinical Centers are requested to present the
following information:

For each year, the Clinical Centers should include the core budget costs and
patient care costs. The core budget which is limited to $150,000 total costs
is expected to cover a minimum 10% effort for the principal investigator, a
small percent effort for other key personnel (nurse, technician, clinic
coordinator, secretary), and travel costs for two people to attend 4 Network
meetings per year in Bethesda, MD. Total costs for the core budget may be
escalated at three percent for future years. Actual patient care costs will
be determined by the specific protocols implemented at each center. For
application purposes, $255,000 (total costs) should be entered on the patient
care cost line on the budget page. This amount will be restricted for this
purpose. Funds released will reflect protocol-specific costs as protocols
are implemented.

For the purpose of the review, centers should provide separate budgets for
each clinical protocol they propose. These budgets should be developed on a
cost per patient basis and include all direct and any applicable facilities
and administrative costs. Costs of recruiting and following patients, costs
for drugs or procedures, and costs for laboratory tests should be part of the
per patient cost of conducting a protocol. Applications should identify the
potential source(s) and cost for any drugs or procedures that are being
considered for clinical protocols. The yearly budget for each protocol should
include the number of patients available for the proposed protocol at the
applicant’s center.

Investigators should prepare budgets only for their own center to conduct the
proposed trial, and not for the entire Network. However, the budget should
state the total number of patients required from the entire network to
complete each proposed trial.

Continuation and level of funding for each Core Clinical Center will be based
on actual recruitment and overall performance. Awards will be subject to
administrative review annually. The entire Network will be reviewed after
approximately three years.

Material to Include in Data Coordinating Center Applications:

To promote development of a collaborative program among the award recipients,
the issues discussed below need to be addressed in each application for a
Data Coordinating Center and will be considered during the review of the
application. This material is in addition to the submission of a research
plan, as described in the section entitled Research Scope and should be
included within the 25 page limit. The Data Coordinating Center application
may include an additional 5 pages to accommodate the clinical protocol
proposal as noted above.

Qualifications and experience. Applicants for the Data Coordinating Center
must demonstrate knowledge in the area of hematopoietic stem cell
transplantation and demonstrated experience coordinating multi-center
clinical trials in all phases: protocol and manual of operations development,
staff training in study procedures, data form development, patient
recruitment strategies, data collection and management, quality assurance,
data analysis, distributed data entry, electronic communications including
web site development and management, administrative management and
coordination. The experience of key personnel should be described.

Study design and management. Data Coordinating Center applicants should
discuss various aspects of study design that would be important in developing
clinical protocols, for example: eligibility criteria; baseline and outcome
measures; methods of randomization; important considerations for sample size
and power calculations; methods and frequency of data collection and entry;
monitoring accuracy of data collection including at least yearly site visits;
quality control procedures including training and certification for multiple
protocols, some of which may occur simultaneously; managing, labeling and
handling of patient samples (see below); and plans for statistical analysis.
Applicants should provide a time line for protocol development and a strategy
for reducing the time required to initiate patient enrollment in new studies.
Experience in and plans for development and use of novel statistical study
designs should be described. Applicants should describe their familiarity
with hematopoietic stem cell transplantation. Plans for coordinating the
Data Safety Monitoring Board and the Protocol Review Committee should be
included.

Patient enrollment at Core Clinical Centers. Propose a method for screening
eligible patients at Core Centers and identifying causes of non-enrollment.
Describe previous experience with strategies to improve accrual in randomized
clinical studies.

Patient enrollment at outside centers. In order to produce the fastest
possible accrual to phase III studies it is desirable that studies be
accessible to as many patients as possible. The applicant should include a
plan to identify interested non-Core transplant centers, evaluate their
ability to enroll patients to a specific protocol, collect data from these
centers, conduct onsite data audits at these centers, and provide per capita
reimbursement for enrollment to these centers .

Patient samples. The applicant should delineate how laboratory specimens
required for specific studies will be handled and be prepared to submit plans
for identifying a central laboratory(ies), establishing a specimen
repository, or obtaining other services as needed for specific protocols.
The costs of obtaining protocol-specific tests or services will be budgeted
as a part of the per patient costs of each Clinical Center. (Costs for tests
that are a routine part of the patients’ clinical care should not be included
and may not be paid from grant funds.) The costs of specimen shipment as
well as laboratory data acquisition and management will be a part of the
budget of the Data Coordinating Center. An estimated shipping and handling
costs per year for specimens should be included in the budget of the Data
Coordinating Center.

Central source of drugs and investigational agents. The applicant should
describe in general terms plans to obtain needed drugs, biologic reagents, or
devices and describe their experience with studies of investigational agents.

Budget and Related Issues for Data Coordinating Center Applicants:

Applicants for the Data Coordinating Center should prepare budgets for five
12 month periods that roughly correspond with the standard coordinating
center responsibilities outlined in other sections of this RFA. For budget
purposes, Data Coordinating Center applicants should assume that in the first
year, all administrative aspects of the Network will be organized and two
protocols will be developed and started. For subsequent years, applicants
should assume that at least four new protocols will be initiated each year.

Data Coordinating Center applicants should include costs for managing the
DSMB and the Protocol Review Committee including the cost of three meetings
per year in Bethesda. In addition, funds for reimbursing non-Core centers for
patient accrual as well as appropriate oversight should be included. The
Data Coordinating Center should budget $50,000 for expenses related to
support for the chair of the Steering Committee. It is estimated that in
addition to the standard data coordinating center responsibilities the
potential per patient reimbursement, laboratory tests and services, and
biologic reagents may cost an additional $500,000 total per year.

The award will be subject to administrative review annually. There will be an
administrative review by NHLBI and NCI after approximately three years to
determine if the network and each of its components has been performing as
envisioned in terms of patient recruitment and implementation of protocols of
importance to the field. It is expected that all protocols will be performed
in a manner consistent with United States Food and Drug Administration
guidelines.

APPLICATIONS NOT CONFORMING TO THESE GUIDELINES WILL BE CONSIDERED
UNRESPONSIVE TO THIS RFA AND WILL BE RETURNED WITHOUT FURTHER REVIEW.

The RFA label available in the PHS 398 application form must be affixed to
the bottom of the face page of the application. 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, to identifying the application as a response to this RFA, check
"YES" in item 2 of page 1 of the application and enter the title " Blood and
Marrow Transplant Clinical Research Network HL- 01-004.”

Submit a signed, typewritten original of the application and three signed
photocopies, in one package to:

CENTER FOR SCIENTIFIC REVIEW
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710
BETHESDA, MD 20892-7710
BETHESDA, MD 20817 (for express/courier service)

At the time of submission, two additional copies of the application must be
sent to Dr. Deborah Beebe at the listing under INQUIRIES.

Applications must be received by March 19, 2001. If an application is
received after this date it will be returned to the applicant without review.

The Center for Scientific Review (CSR) will not accept any application in
response to this RFA that is essentially the same as one currently pending
initial review, unless the applicant withdraws the pending application. This
does not preclude the submission of substantial revisions of an application
already reviewed, but such applications must include an introduction
addressing the previous critique.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by the CSR and
for responsiveness by NHLBI and NCI staff. Incomplete and/or nonresponsive
applications will be returned to the applicant without further review.
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 Affairs, NHLBI, in accordance with the
review criteria stated below. The roster of the initial review group will be
available via the NHLBI home page approximately two weeks prior to the
review.

As part of the initial merit review, all applications will receive a written
critique and undergo a review in which only those applications deemed to have
the highest scientific merit will be discussed and assigned a priority score.
The National Heart, Lung and Blood Advisory Council and the National Cancer
Advisory Board will perform a second level of review.

Applications will be judged primarily on the scientific quality of the
application, however, the scientific merit of the proposed research plan will
not be the sole criterion for selection of a Clinical Center. Applicants are
encouraged to present their own ideas on how best to meet the goals of the
Network, but they are expected to address issues identified under APPLICATION
PROCEDURES of the RFA.

Review Criteria for Core Clinical Center Applications

Research plan. Appropriateness of proposed protocols, need for the network
to accomplish the proposed protocol, relevance and importance of the research
questions, preliminary results that justify the proposed end points and
sample size, and likelihood that accrual could be accomplished in three
years.

Qualifications and experience. The expertise, training, and experience of
the investigators and staff in blood and marrow transplantation clinical
trials, evidence of understanding of randomized, multi-center trials,
administrative abilities of the Principal Investigator, study nurse and/or
data coordinator, and the time they plan to devote to the program for the
effective function of the Clinical Research Network.

Patient access and study population. The availability of at least 35
allogeneic transplants at the applicant’s institution per year; the number
that will be eligible for Network protocols; plans for the recruitment and
retention of subjects; plans to ensure appropriate representation by ethnic
group, age, and gender; the description of competing protocols, and the
strategy for allocating patients between them.

Willingness to participate in the Network. Applicant institution’s history
of collaborative research, depth of commitment, willingness to randomize
patients, and ability to work with other Network Centers, NHLBI, and NCI.

Institutional resources for patient care and follow-up. Adequacy of
institutional resources including personnel, space, and special laboratory
facilities.

The reasonableness of the proposed budget and duration in relation to the
proposed research.

The adequacy of the proposed protection for humans, animals or the
environment, to the extent they may be adversely affected by the project
proposed in the application.

Further considerations for the review include: access to patients, multi
disciplinary nature of the proposed studies, the discussion of considerations
relevant to this RFA, and a demonstrated willingness on the part of the
investigators to work as part of the Clinical Research Network and with the
NHLBI and NCI Project Scientists.

Review Criteria for Data Coordinating Center Applications

Research plan. Demonstrates understanding of the scientific, statistical,
logistical, and technical issues underlying multi-center studies, including
issues relating to treatment and management of transplant subjects; and
demonstrates leadership in study design and statistics, data acquisition and
management, data quality control, data analysis, handling and quality
control of laboratory specimens, and network coordination.

Qualifications and experience. The expertise, training, and experience of the
investigators and staff, including the administrative abilities of the
Principal Investigator, co- investigator, and the time they plan to devote to
the program for the effective coordination of the Clinical Research Network.

Study management. The administrative, supervisory, and collaborative
arrangements for achieving the goals of the program, including willingness to
cooperate with the participating Clinical Centers and the NHLBI and NCI.
This includes the ability to assist Core Clinical Centers with recruitment
problems, and identify and subcontract with non-Core clinical centers to meet
accrual goals.

Willingness to participate in the Network. Applicant institution’s history
of collaborative research, depth of commitment, and ability to work with
other Network Centers, NHLBI, and NCI.

Environment. Facilities, equipment, and organizational structure to
effectively coordinate Clinical Research Network activities and assist
Clinical Centers in implementing the Clinical Research Network protocols,
providing for specialized laboratory testing, and collecting data. This
includes but is not limited to development of repositories, conduct of lab
tests and studies, and obtaining study drugs or investigational agents.

The reasonableness of the proposed budget and duration in relation to the
proposed research.

The adequacy of the proposed protection for humans, animals or the
environment, to the extent they may be adversely affected by the project
proposed in the application.

Further considerations for the review include: plans for access to patients,
multi disciplinary nature of the proposed studies, the discussion of
considerations relevant to this RFA, and a demonstrated willingness on the
part of the investigators to work as part of the Clinical Research Network
and with the NHLBI and NCI Project Scientists.

Schedule

Letter of Intent Receipt Date: February 21, 2001
Application Receipt Date: March 19, 2001
Council Review: August/September, 2001
Anticipated Award Date: September 30, 2001

AWARD CRITERIA

Factors that will be considered in making awards include: a) the scientific
merit of the proposed program as determined by peer review, the multi
disciplinary nature of the proposed studies, and the quality of meeting the
special requirements stated in this RFA; b) relevance to the overall
programmatic balance and priorities of NHLBI and NCI, and sufficient
compatibility of features proposed in the research plan and qualifications of
the investigators to make a collaborative program within the Network a
reasonable likelihood; c) the inclusion by the network of gender and minority
participants in a manner consistent with the disease prevalence in question
in the U.S. population; and d) the availability of funds.

INQUIRIES

Inquiries concerning this RFA are encouraged. The opportunity to clarify any
issues or questions from potential applicants is welcome.

Direct inquiries regarding programmatic issues to:

Dr. Charles M. Peterson
Division of Blood Diseases and Resources
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Suite 10018, MSC 7950
Bethesda, Maryland 20892-7950
Telephone: (301) 435-0050
FAX: (301) 480-0868
E-mail: petersoc@nih.gov

Dr. Roy S. Wu
Division of Cancer Treatment & Diagnosis
National Cancer Institute
Executive Plaza North, Room 734
6130 Executive Boulevard
Bethesda, MD 20892
Telephone: (301) 496-8866
FAX: (301) 480-4663
Email: Wur@ctep.nci.nih.gov

Direct inquiries regarding review matters, send letter of intent, and two
copies of the application to:

Dr. Deborah Beebe
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Suite 7178, MSC 7924
Bethesda, Maryland 20892-7924 (20817 for express mail)
Telephone: (301) 435-0270
FAX: (301) 480-3541
E-mail: BeebeD@nhlbi.nih.gov

Direct inquiries regarding fiscal matters to:

Jane Davis
Grants Operations Branch
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Suite 7174, MSC 7926
Bethesda, MD 20892-7926
Telephone: (301) 435-0166
FAX: (301) 480-3310
E-mail: davisj@nih.gov

Authority and Regulations

This program is described in the Catalog of Federal Domestic Assistance, No.
93.839. Awards are made under authorization of the Public Health Service
Act, Title IV, Part A (Public Law 78-410, amended by Public Law 99-158, 42
USC 241 and 285) and administered under NIH grants policies and Federal
Regulations 42 CFR 52 and 45 CFR Part 74. This program is not subject to the
intergovernmental review requirements of Executive Order 12372 or a Health
Systems Agency Review.

The NIH strongly encourages all grant and contract 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 NIH mission to protect and advance the physical and mental health of
the American people.

Weekly TOC for this Announcement
NIH Funding Opportunities and Notices

	Office of Extramural Research (OER)			National Institutes of Health (NIH) 9000 Rockville Pike Bethesda, Maryland 20892			Department of Health and Human Services (HHS)
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