NIH Guide: THALASSEMIA (COOLEY'S ANEMIA) CLINICAL RESEARCH NETWORK

THALASSEMIA (COOLEY'S ANEMIA) CLINICAL RESEARCH NETWORK

Release Date: March 11, 1999 (see NOT-HL-03-017)

RFA: HL-99-016

P.T.

National Heart, Lung, and Blood Institute

Letter of Intent Receipt Date: June 1, 1999
Application Receipt Date: September 16, 1999

PURPOSE

The National Heart, Lung, and Blood Institute (NHLBI) invites applications to
participate in the establishment of a Thalassemia Clinical Research Network
(network) of interactive clinical research groups. This network will allow for
the efficient evaluation of novel treatment methods and management strategies
of potential benefit for children and adults with thalassemia. The objective
of this Request for Applications (RFA) is to establish and maintain (1) the
infrastructure required for a network of five to six clinical centers to
perform multiple clinical trials for persons with thalassemia, and (2) a Data
Coordinating Center for the network. This is a one time solicitation to
support a Thalassemia Clinical Research Network for five years.

HEALTHY PEOPLE 2000

The Public Health Service (PHS) is committed to achieving the health promotion
and disease prevention objectives of "Healthy People 2000," a PHS-led national
activity for setting priority areas. This RFA, Thalassemia Clinical Research
Network, is related to the priority areas of chronic disabling conditions and
clinical prevention services. Potential applicants may obtain a copy of
"Healthy People 2000" (Full Report: Stock No. 017-001-00474-0 or Summary
report: Stock No. 017-001-00473-1) through the Superintendent of Documents,
Government Printing Office, Washington, DC 20402-9325 (telephone 202-512-
1800), or at http://www.crisny.org/health/us/health7.html.

ELIGIBILITY REQUIREMENTS

Applications may be submitted from the United States of America and Canada.
This geographic constraint will be necessary because of the need for close
communication among members of the program, the requirement for frequent
steering committee meetings, and 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.

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 grant programs
of the National Institutes of Health (NIH) will apply to grants awarded under
this RFA. Among the disciplines and expertise that may be appropriate for
this program are pediatrics, internal medicine, hematology, pharmacology,
therapeutic development, and clinical trials management.

Awards for a 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 done independently of data acquisition. The same institution may
apply for both a 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 under the section entitled RESEARCH OBJECTIVES.

The total project period for applications submitted in response to this RFA
will be five years. This RFA is a one-time solicitation. Although not co-
sponsoring this RFA, other Institutes (National Institute of Diabetes
Digestive and Kidney Diseases, and National Institute of Child Health and
Human Development) have an interest in the research area discussed in this
RFA. Future applications in this research area will be assigned based on NIH
referral guidelines.

The anticipated award date is July 2000. It is anticipated that the award for
each Clinical Center will be up to $330,000 total costs per year. This
includes up to $150,000 total core costs and up to $180,000 for total patient
costs depending on per patient costs. The award for the Data Coordinating
Center will be up to $520,000 total costs per year.

FUNDS AVAILABLE

An estimated five to six awards for Clinical Centers and one award for a Data
Coordinating Center will be made under this RFA. A maximum of about $12.5
million (total costs) over a five-year period will be awarded for the Clinical
Centers and the Data Coordinating Center. 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 will also vary in all years. Future year costs will be
distributed based on the recommended protocols.

Although the financial plans of the NHLBI 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 applications of outstanding scientific
and technical merit. 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

Cooley's anemia (beta-thalassemia major, hereafter referred to as thalassemia)
is a severe, inherited blood disorder characterized by a quantitative defect
in the synthesis of the beta chain of hemoglobin caused by any one of more
than 100 known mutations in and around the beta globin gene cluster. The
disease is characterized by severe anemia beginning in the first six to twelve
months of life. If untreated, the life expectancy is less than five years of
age. Chronic red blood cell transfusions to maintain hemoglobin levels
between nine and 11 gm/dl ("hypertransfusion") alleviate the anemia and
partially suppress erythropoiesis. The regular administration of red blood
cells also improves growth, delays or prevents enlargement of the liver, and
spleen, and prevents the development of bone abnormalities that cause
fractures as well as disfiguring changes known as Cooley's facies.
Transfusions carry risks of alloimmunization, iron overload, an blood
transmitted infections. In the absence of effective iron chelation therapy,
iron overload leads to numerous complications including delayed or absent
sexual development, diabetes mellitus, cirrhosis, cardiac arrhythmias, and
congestive heart failure. Non-chelated or poorly chelated patients usually die
of heart disease by 20 to 30 years of age. The majority of patients with
thalassemia major transfused prior to the late 1980's are infected with
hepatitis C, and this may also prove to be a significant cause of morbidity
and mortality in this hematologic disorder.

The addition of chelation therapy with deferoxamine to the treatment of
Cooley's anemia has dramatically improved the outcome for affected patients.
With regular chelation therapy, the accumulation of excessive iron can be
prevented. Studies have demonstrated that well-chelated patients have normal
or only modest increases in liver iron, improved growth, sexual development,
and most importantly, a markedly reduced chance of developing iron induced
heart disease.

In the past few years, several new approaches to the treatment of thalassemia
have included marrow or stem cell transplantation, the use of young red blood
cells ("neocytes" for transfusion), maintenance of a higher pre-transfusion
hemoglobin level, new iron chelators, and the use of drugs such as
hydroxyurea, erythropoietin, and butyrate compounds.

It is recognized that even with a clinical network, the number of patients
with Cooley's Anemia who can be enrolled in a research protocol is likely to
be small. Therefore, although a randomized clinical trial may be the preferred
way of assessing the clinical benefits of a new therapy, it may not be
feasible in some instances, even using biomarkers or other surrogate outcome
measures. Depending upon the specific questions being addressed, other study
designs might be appropriate. These might include pre- and post-treatment
assessment or historical control studies. In all cases, the proposed design,
including sample size would be evaluated by the Protocol Review Committee.

There is an urgent need to evaluate new and existing therapeutic approaches
for persons with thalassemia, and to disseminate the findings to health care
professionals, patients and the public. There are several reasons why a
thalassemia clinical research network will accelerate clinical research and
meet this need. The highly variable and sometimes complicated clinical
manifestations of thalassemia often make it difficult to accumulate a large
number of comparable patients in one center. Further, uniformity in treatment
protocols may reduce the number of patients needed at each clinical center.
Also, the Thalassemia Clinical Research Network mechanism will help pool the
necessary clinical expertise and administrative resources to facilitate the
conduct of multiple and novel therapeutic trials in a timely, efficient
manner. This, in turn, would promote rapid dissemination of research findings
to health care professionals.

Organization of the Thalassemia Clinical Research Network

The Thalassemia Clinical Research Network will be a cooperative network of
five-six Clinical Centers, one Data Coordinating Center, and the Division of
Blood Diseases and Resources, NHLBI. Clinical Centers will be responsible for
proposing protocols that could be adapted by the network, participating in
their overall development, conducting the research, and disseminating research
findings. All individual Clinical Centers will be required to participate in
a cooperative and interactive manner with one another and with the Data
Coordinating Center in all aspects of the Thalassemia Clinical Research
Network. A separate Data Coordinating Center will support protocol
development and provide sample size calculations, statistical advice, common
questionnaires, data analysis, and coordinate the activity of the Data and
Safety Monitoring Board, The Protocol Review Committee and overall study
coordination and quality assurance.

A Steering Committee will be the main governing body of the Thalassemia
Clinical Research Network and, at a minimum, will be composed of the principal
investigators of the Clinical Centers and the Data Coordinating Center and the
NHLBI Project Scientist. Each Clinical Center, the Data Coordinating Center
and the NHLBI will have one vote. The Steering Committee may meet as often as
three to six times in the first 12 months of the study, and two to four times
per year thereafter. All major scientific decisions will be determined by
majority vote of the Steering Committee. The Chairperson, who will be someone
other than an NHLBI staff member and may be someone other than a principal
investigator, will be selected by the end of the second meeting of the
Steering Committee. The first meeting of the Steering Committee will be
convened by the NHLBI Project Scientist. The Steering Committee will have
primary responsibility for the general organization of the Thalassemia
Clinical Research 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.
For each protocol, one Clinical Center will take the lead responsibility for
drafting the protocol, although the Steering Committee will provide input and
will be responsible for assuring development of a common protocol to be
implemented by the Clinical Centers. Subcommittees of the Steering Committee
will be established as necessary; for example, it is envisioned that a
Publications and Presentations Committee will facilitate and supervise
preparation of manuscripts prior to submission for publication.

An independent Protocol Review Committee, established by the NHLBI, will
provide peer review for each protocol. A Data Safety Monitoring Board (DSMB),
also established by the NHLBI with input from the Steering Committee, will
monitor patient safety and review performance of each study. As a part of its
monitoring responsibility, the DSMB will submit recommendations to the NHLBI
regarding the continuation of each study.

Each protocol will be implemented in two or more of the Clinical Centers,
depending on the number of patients needed for the study. As specific
protocols are developed, support will depend on the availability of funds and
will be provided on a per patient basis. All the Clinical Centers must be
willing to pursue this funding arrangement for each new protocol conducted.
Clinical protocols must be approved by local institutional review boards and
the Thalassemia Clinical Research Network Protocol Review Committee before
initiation. The exact number of protocols supported in the five year program
will depend on the nature and extent of the investigations proposed by the
Thalassemia Clinical Research Network Steering Committee.

Research Scope

The objective of this RFA is to establish a Thalassemia Clinical Research
Network that will accelerate research in the management of thalassemia,
standardize existing treatments, and evaluate new ones. The emphasis will be
on clinical trials that help identify optimal therapy. Therapeutic trials may
involve investigational drugs, drugs already approved but not currently used,
and drugs currently used. All projects must be completed within the 5 year
duration of this research program.

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

o Are given drugs, vaccines, or other therapies useful in the management of
Thalassemia?

o How can undesirable sequelae of transfusions be prevented and/or managed?

o Are there objective measures of optimum transfusion and chelation?

o Are there new chelators or regimens that warrant testing?

o Does hydroxyurea have a role in thalassemia management?

o Do inducers of hemoglobin F have a role in thalassemia?

o Can safety be increased for transplantation of stem cells from bone marrow,
cord, or peripheral blood in patients with thalassemia?

o Can long-term sequelae of thalassemia or iron overload be better prevented
or ameliorated?

o Are there behavioral or psychological issues that may be important in self
care?

o Are there genetic modifiers of the disease or response to therapy that are
important for the treatment of thalassemia?

o Are there gene therapies that warrant clinical testing?

THESE ARE EXAMPLES ONLY. APPLICANTS SHOULD NOT FEEL LIMITED TO THE SUBJECTS
MENTIONED ABOVE AND ARE ENCOURAGED TO SUBMIT OTHER TOPICS PERTINENT TO THE
OBJECTIVES OF THE RFA. It is not the intent of this network to provide
support for only one or two protocols that run for the entire five years.
Multiple trials will be conducted, possibly two to four a year. It is
anticipated that in the initial year, trials will be selected from the studies
proposed by the successful applicants. However, a decision to fund a
particular Clinical Center will not commit the Thalassemia Clinical Research
Network to develop that group's clinical protocol.

Each Clinical Center applicant should propose a research plan that includes
two protocols as models that could potentially be used in the network
environment. The protocols should demonstrate knowledge in the field of
thalassemia. Each protocol should require sufficient subjects to necessitate
the use of a network with multicenter participation. Applicants should
indicate knowledge of the number of patients required for each study based on
sample size calculations. One protocol must be a short term (one year or
less) and one a long term (one to three years) investigation of thalassemia.
The research plan should follow the instructions in the PHS 398 application
form (revised 4/98; https://grants.nih.gov/grants/forms.htm).For each of the two
protocols include a description in approximately two to three pages 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.

The applicant should indicate for each protocol how many patients are
available in the applicant's center and how many will be required from the
entire network. In the discussion of outcome measures, it will be important
to indicate appropriate objective measures of primary and secondary outcome.
Applicants are encouraged to explore, within the context of their proposed
protocols, new technologies to monitor disease progression and response to
therapy. The relevant technology should be presently available for each
protocol proposed during the 5 years of funding. It will also be important to
include strategies to assure adherence to therapy as part of the protocol.

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 and
a recipient, in which substantial NHLBI scientific and/or programmatic
involvement with the recipient is anticipated during performance of the
activity. The NHLBI 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 these collaborative actions
with the NHLBI Project Scientist toward achieving the project objectives. It
is anticipated that these terms and conditions will enhance the relationship
between the NHLBI staff and the principal investigator(s), and will facilitate
the successful conduct and completion of the study. These agreements will be
in addition to, and not in lieu of, the relevant NIH procedures for grants
administration. The terms will be as follows:

1. The awardee(s) will have lead responsibilities in all aspects of their
protocols, including any modification of study design, conduct of the study,
quality control, data analysis and interpretation, preparation of
publications, and collaboration with other investigators, unless otherwise
provided for in these terms or by action of the Steering Committee.
Modifications and ancillary protocols will be approved by the Steering
Committee and the Data Safety Monitoring Board.

2. The NHLBI Project Scientist will serve on the Steering Committee; he/she or
another NHLBI scientist may serve on other study committees, when appropriate.
The NHLBI Project Scientist (and the other cited NHLBI scientists) may work
with awardees on issues coming before the Steering Committee and, as
appropriate, other committees, e.g., recruitment, intervention, follow-up,
quality control, standards and methods, adherence to protocol, assessment of
problems affecting the study and potential changes in the protocol, interim
data and safety monitoring, final data analysis and interpretation,
preparation of publications, and development of solutions to major problems
such as insufficient participant enrollment.

3. Awardee(s) agree to the governance of the study through a Steering
Committee. Steering Committee voting membership shall consist of the principal
investigators (i.e., cooperative agreement awardees) and the NHLBI Project
Scientist. Meetings of the Steering Committee will ordinarily be held by
telephone conference call or in the Washington DC Metropolitan Area.

4. A Data and Safety Monitoring Board will be appointed by the Director, NHLBI
to provide overall monitoring of interim data and safety issues; the Steering
Committee may nominate members for this Board. Meetings of the Data and
Safety Monitoring Board will ordinarily be held in Bethesda, MD. The NHLBI
Project Scientist shall serve as Executive Secretary to the Board.

5. Awardees will retain custody of and have primary rights to their data
developed under these awards, subject to Government rights of access
consistent with current HHS, PHS, and NIH policies. The collaborative
protocol and governance policies will call for the continued submission of
data centrally to the coordinating center for a collaborative database; the
submittal of copies of the collaborative data sets to each principal
investigator upon completion of the study; procedures for data analysis,
reporting and publication; and procedures to protect and ensure the privacy of
medical and genetic data and records of individuals. The NHLBI Project
Scientist, on behalf of the NHLBI, will have the same access, privileges and
responsibilities regarding the collaborative data as the other members of the
Steering Committee.

6. 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 support; or special
access to project results, data, findings or resources -- may be advantageous
and appropriate. However, except for licensing of patents or copyrights,
support or involvement of any third party will occur only following
notification of, and concurrence by, NHLBI.

7. 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 and the NHLBI. However, during or
within three years beyond the end date of the project period of NHLBI support,
unpublished data, unpublished results, data sets not previously released, or
other study materials or products are to be made available to any third party
only with the approval of the Steering Committee and in accordance with
paragraph 6.

8. Upon completion of the project, the Data Coordinating Center is expected
to put all study intervention materials and procedure manuals into the public
domain and/or make them available to other investigators, according to the
approved plan for making data and materials available to the scientific
community and the NHLBI, for the conduct of research at no charge other than
the costs of reproduction and distribution.

9. The NHLBI reserves the right to terminate or curtail the study (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 cannot concur, (d) reaching a major study endpoint
substantially before schedule with persuasive statistical significance, or (e)
human subject ethical issues that may dictate a premature termination.

10. Any disagreement that may arise in scientific/programmatic matters (within
the scope of the award), between award recipients and the NHLBI may be brought
to arbitration. An arbitration panel will be composed of three members--one
selected by the Steering Committee (with the NHLBI member not voting) or by
the individual awardee in the event of an individual disagreement, a second
member selected by NHLBI, and the third member selected by the two prior
members. This special arbitration procedure in no way affects the awardee's
right to appeal an adverse action that is otherwise appealable in accordance
with the PHS regulations at 42 CFR part 50, Subpart D and HHS regulation at 45
CFR part 16, or the rights of NHLBI under applicable statutes, regulations and
terms of the award.

11. 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
administration policy statements.

INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH STUDIES

It is the policy of the NIH that women and members of minority groups and
their subpopulations must be included in all NIH supported biomedical and
behavioral research projects involving human subjects, unless a clear and
compelling rationale and justification is provided 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 follow the "NIH Guidelines for Inclusion of
Women and Minorities as Subjects in Clinical Research," which have been
published in the Federal Register of March 28, 1994 (FR 59 14508-14513), and
in the NIH Guide for Grants and Contracts of March 18, 1994, Volume 23, Number
11 and available on the web at:
https://grants.nih.gov/grants/guide/notice-files/not94-100.html.

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 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:
https://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.

LETTER OF INTENT

Prospective applicants are asked to submit, by June 1, 1999, 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 staff to estimate the potential review workload and avoid conflict of
interest in the review.

The letter of intent is to be faxed or mailed to Dr. C. James Scheirer 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 and 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 301-710-0267, E-mail: GrantsInfo@nih.gov. The PHS 398 application kit is also
available on the Internet at https://grants.nih.gov/grants/forms.htm

Material to Include in the Application

Clinical Center Applicants:

To promote development of a collaborative program among the award recipients,
the issues discussed below need to be addressed in each application for a
Clinical Center. This material is in addition to the submission of a research
plan, as described in the section entitled Research Scope.

o Qualifications and experience. Applicants for Clinical Centers must have
experience and expertise to conduct clinical studies in thalassemia.
Prospective Clinical Centers must have an established research program in the
area of thalassemia.

o Study population. Clinical Center applicants must have access to at least
30 persons with thalassemia. The Thalassemia Clinical Research Network should
include children and approximately 50 percent females. 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 variants of thalassemia, and recruitment source. Access to at least
30 patients for various protocols over the five year period is expected, but
it is not anticipated that all 30 patients will be enrolled in research
protocols at any one time, and it is possible that an individual patient may
be enrolled in more than one study. Patient access may be accomplished by
establishing links with other groups besides the applicant's institution.
There must be a well described plan to link the individual Clinical Centers
with community health care providers such as HMOs, clinics, or private
practice physicians to ensure adequate numbers patients for clinical studies
of therapeutic agents and management strategies.

Applicants from institutions that have a General Clinical Research Center
(GCRC) funded by the NIH National Center for Research Resources may wish to
identify the GCRC as a resource for conducting the proposed research. If so,
a letter of agreement from either the GCRC Program Director or Principal
Investigator should be included with the application.

o Specific laboratory tests will be budgeted as a part of the per patient
costs of each Clinical Center.

o Willingness to participate in the Thalassemia Clinical Research Network.
Applicants should state their general support of collaborative research and
interaction with other Clinical Centers, the NHLBI, and the Data Coordinating
Center through this network concept. Applicants should discuss their
willingness, and that of the institutions involved, to pursue a per patient
basis (capitation) of operational costs for each protocol. Clinical Center
applicants must be able to interact with the Data Coordinating Center to
transmit and edit data and should discuss their capability to participate in a
distributed data entry system.

o Institutional resources for patient care and follow-up including personnel,
space, and special laboratory facilities should be described.

Data Coordinating Center Applicants:

o Qualifications and experience. Applicants for a data coordinating center
must demonstrate experience in the area of hematology and demonstrated
expertise coordinating multi-center clinical trials in all phases: protocol
and manual of operations development, staff training in study procedures,
research instrument development, data collection and management, quality
assurance, data analysis, distributed data entry, electronic communications,
administrative management and coordination.

o 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 making sample
size and power calculations; methods and frequency of data collection and
entry; monitoring accuracy of data collection; quality control procedures
including training and certification for multiple protocols, some of which may
occur simultaneously; managing labeling and handling of blood samples (see
below); and plans for statistical analysis. Applicants should also describe
their familiarity with thalassemia and plans for managing the Data Safety
Monitoring Board and the Protocol Review Committee. Approximately $25,000
should be included for managing the Data Safety Monitoring Board and the
Protocol Review Committee.

o The Data Coordinating Center should delineate how laboratory specimens will
be handled. Laboratories responsible to the Data Coordinating Center will
manage specimens and laboratory studies as required by the Steering Committee.
The costs of performing specific laboratory tests will be budgeted as a part
of the per patient costs of each Clinical Center. 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 of $25,000 for specimens should be included in the budget of
The Data Coordinating Center.

BUDGET AND RELATED ISSUES

Applicants should complete the budget information as directed in the PHS 398
application form.

Clinical Center Applicants:

Clinical Center applicants should consider the following additional issues
regarding budgets. The underlying concept of the Thalassemia Clinical
Research Network is that a core effort is essential to maintain the
infrastructure required to perform multiple clinical trials. Based on this
approach, it is estimated that the individual Clinical Centers will require a
minimum level of effort to sustain the organizational aspects of the
Thalassemia Clinical Research Network. Therefore, individual Clinical Centers
should submit requests for a CORE BUDGET not to exceed $150,000 total costs
per year. It is anticipated that this core budget will cover a minimum 10%
effort for the principal investigator, and a small percent effort for other
key personnel (nurse, technician, clinic coordinator, secretary), and travel
costs for two people to attend three Thalassemia Clinical Research Network
meetings a year in Bethesda, MD. These costs may be distributed in their
application and include appropriate justification. Total costs for the core
budget may be escalated at three percent for future years.

In addition to the core budget, each Clinical Center will be provided funds
for implementation of protocols; this support will be provided for each
protocol on a per successfully enrolled patient basis. The precise number of
protocols conducted over the five years will be determined by the Thalassemia
Clinical Research Network Steering Committee and will depend on availability
of funds. It is anticipated that after the first year, two to four protocols
may be active each year. Clinical Centers may request PATIENT CARE costs.
This amount should be placed in the patient care category. Patient care costs
may be escalated at three percent for future years. Allowable total costs for
each clinical center (core costs, costs per patient to conduct the protocols,
and indirect costs) will be $330,000 a year.

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

o For each year, the Clinical Centers should include the core budget costs
(not to exceed $150,000 total costs) and patient care costs (not to exceed
$180,000 total costs). Estimated protocol implementation costs for Year 1
should be based on the two proposals presented in the applicants research
plan. A table should be included showing estimated costs per patient for
conducting each protocol.

The budget for each clinical protocol should be developed on a cost per
patient basis and include all direct and any applicable facilities and
administrative costs. Costs of drugs or laboratory tests should be part of the
per patient cost of conducting a protocol. Applications should identify the
potential source(s) for any drugs or substances that are being considered for
clinical protocols that are currently unavailable commercially. Investigators
should only prepare budgets for their own Clinical Center to conduct the
proposed trial, and not for the entire Thalassemia Clinical Research Network.
The applicant should state the total number of patients required by the entire
network to complete each proposed trial. The yearly budget for the
applicant's center should include the number of patients available for the
proposed protocol at the applicants center. A budget based on the costs per
patient for recruiting and maintaining the specified number of subjects at the
applicant's center should be included for each protocol.

Note that ongoing annual budgets for protocols will be based on the protocols
approved by the Thalassemia Clinical Research Network Steering Committee and
will be funded through a per patient basis (capitation) funding mechanism.
The individual clinics will be expected to project patient enrollment for a
specific protocol during a specified time frame; continuation and level of
funding for each Clinical Center will be based on actual recruitment and
overall performance.

Awards will be subject to administrative review annually.

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 Thalassemia Clinical Research Network will be
organized and one protocol will be developed and started. For subsequent
years, applicants may assume that two to four protocols a year will be active,
i.e. either in the protocol development, implementation, or analysis and
writing phase. Data Coordinating Center applicants should include costs for
managing the DSMB and the Protocol Review Committee including the cost of
meeting three times/year in Bethesda.

The award will be subject to administrative review annually. 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 " Thalassemia
Clinical Research Network HL-99-016.

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. C. James Scheirer at the listing under INQUIRIES.

Applications must be received by September 16, 1999. 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. 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, assigned a priority score, and
receive a second level review by the National Heart, Lung and Blood Advisory
Council.

Review Criteria

Clinical Centers:

The goals of NIH-supported research are to advance our understanding of
biological systems, improve the control of disease, and enhance health. In
the written comments, reviewers will be asked to discuss the following aspects
of the application in order to judge the likelihood that the proposed research
will have a substantial impact on the pursuit of these goals. Each of these
criteria will be addressed and considered in assigning the overall score,
weighting them as appropriate for each application. Note that the application
does not need to be strong in all categories to be judged likely to have major
scientific impact and thus deserve a high priority score. For example, an
investigator may propose to carry out important work that by its nature is not
innovative but is essential to move a field forward.

o Significance: Does this study address an important problem? If the aims
of the application are achieved, how will scientific knowledge and care of the
person with thalassemia be advanced? What will be the effect of these studies
on the concepts or methods that drive this field?

o Approach: Are the conceptual framework, design, methods, and analyses
adequately developed, well-integrated, and appropriate to the aims of the
project? Does the applicant acknowledge potential problem areas and consider
alternative approaches?

o Innovation: Does the project employ novel concepts, approaches or methods?
Are the aims original and innovative? Does the project challenge existing
paradigms or develop new methodologies or technologies?

o Investigator: Is the investigator appropriately trained and well suited to
carry out this work? Is the work proposed appropriate to the experience level
of the principal investigator and key personnel?

o Environment: Does the scientific environment in which the work will be
done contribute to the probability of success? Do the proposed experiments
take advantage of unique features of the scientific environment or employ
useful collaborative arrangements? Is there evidence of institutional support
and is there a tradition of thalassemia research and clinical care?

In addition to the above criteria, in accordance with NIH policy, all
applications will also be reviewed with respect to the following:

o The adequacy of plans to include both genders, minorities and their
subgroups, and children as appropriate for the scientific goals of the
research. Plans for the recruitment and retention of subjects will also be
evaluated.

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

o 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.

The initial review group will also examine the provisions for the protection
of human subjects and the safety of the research environment.

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 submit and describe their own ideas on how best to meet the
goals of the Thalassemia Clinical Research Network, but they are expected to
address issues identified under APPLICATION PROCEDURES of the RFA. 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 Thalassemia Clinical Research Network and with the NHLBI
Project Scientist.

Data Coordinating Center:

Considerations for the review of Data Coordinating Center Applicants include
the following issues:

o Understanding of the scientific, statistical, logistical, and technical
issues underlying multi center studies, including issues relating to treatment
and management of thalassemia, and taking a leadership role in the area of
study design, statistics, logistics, data acquisition and management, handling
of laboratory specimens, quality control, data analysis, and network
coordination.

o Adequacy of the proposed plans for acquisition, transfer, management, and
analysis of data, quality control of data collection and monitoring, and
overall coordination of Thalassemia Clinical Research Network activities.

o 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 Thalassemia Clinical Research Network.

o 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.

o Facilities, equipment, and organizational structure to effectively
coordinate Thalassemia Clinical Research Network activities and assist
Clinical Centers in implementing the Thalassemia Clinical Research Network
protocols, providing for specialized laboratory testing, and collecting data.

o Appropriateness of the budget for the work proposed.

Schedule

Letter of Intent Receipt Date: June 1, 1999
Application Receipt Date: September 16, 1999
Council Review: May 2000
Anticipated Award Date: July 2000

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 the NHLBI and sufficient compatibility
of features proposed in the research plan and qualifications of the
investigators to make a collaborative program within the Thalassemia Clinical
Research Network a reasonable likelihood; and c) 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:

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

Direct inquiries regarding review matters to:

James Scheirer, Ph.D.
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Suite 7220, MSC 7924
Bethesda, MD 20892-7924
Telephone: (301) 435-0266
FAX: (301) 480-3541
Email: js110j@ nih.gov

Direct inquiries regarding fiscal matters to:

Ms. Jane Davis
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
Email: davisj@gwgate.nhlbi.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 PHS 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 PHS 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 PHS mission to protect and advance the physical and mental health of
the American people.

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	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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