FREQUENT HEMODIALYSIS CLINICAL TRIALS 

RELEASE DATE:  December 4, 2002
 
RFA:  DK-03-005 (Reissued as RFA-DK-07-503)
 
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
 (http://www.niddk.nih.gov)
 
LETTER OF INTENT RECEIPT DATE: February 14, 2003

APPLICATION RECEIPT DATE: March 14, 2003
 
THIS RFA CONTAINS THE FOLLOWING INFORMATION

o Purpose of this RFA
o Research Objectives
o Mechanism(s) of Support 
o Funds Available
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Special Requirements
o Where to Send Inquiries
o Letter of Intent
o Submitting an Application
o Peer Review Process
o Review Criteria
o Receipt and Review Schedule
o Award Criteria
o Required Federal Citations:

PURPOSE OF THIS RFA

The Division of Kidney, Urologic and Hematologic Diseases (DKUHD) of 
the National Institute of Diabetes and Digestive and Kidney Diseases 
(NIDDK) invites cooperative agreement applications for a Data and 
Analysis Coordinating Center (DACC) and two Coordinating Clinical 
Centers (CCCs) to design, develop and implement clinical treatment 
trials of frequent hemodialysis for patients with end stage renal 
disease (ESRD). The DACC and CCCs will propose trial designs for the 
studies.  It is anticipated that two trials will be initiated, one 
comparing short daily hemodialysis with conventional dialysis and one 
comparing long nocturnal dialysis with conventional dialysis.  The goal 
of the RFA is to test the feasibility of randomizing a representative 
sample of dialysis patients into either (a) conventional three times 
per week dialysis, or (b) one of the two forms of frequent dialysis 
named above and to obtain preliminary data on the impact of these 
modalities on patient well-being.  It is expected that patients will be 
followed for a minimum of six months and that intermediate outcomes 
will be tracked such as anemia, nutritional status, blood pressure, 
left ventricular hypertrophy, exercise tolerance, medication use, 
hospitalizations, etc.  Based on the results of these trials, NIDDK 
will determine the advisability of continuing with a large scale trial 
of daily dialysis, powered to measure the impact of more frequent 
dialysis on hard endpoints, such as mortality and/or cardiovascular 
outcomes.

The structure of the trials will be determined in part by the 
proposals.  However, it is expected that the DACC will be responsible 
for coordinating the project design, monitoring data collection, and 
statistical analyses.  Each CCC will be responsible for enrolling 
patients into the trials, monitoring the dialysis interventions, and 
data collection.  It is not necessary that a CCC be able to enroll the 
entire patient cohort at a single site.  A CCC may work out cooperative 
arrangements with a network of dialysis providers to reach enrollment 
goals.  It is expected that CCCs will be given a fixed payment for the 
infrastructure for the trial and variable payments based on attaining 
enrollment goals.
 
RESEARCH OBJECTIVES

A. Background

End stage renal disease afflicts approximately 380,000 Americans. Most 
are receiving hemodialysis three times per week. This frequency of 
hemodialysis, while conventional and capable of sustaining life, has no 
solid scientific basis. Although this schedule is compatible with 
prolonged survival for some patients, the annual mortality rates are 
quite high for the entire population of ESRD patients. 

More frequent hemodialysis has been employed by some centers in small 
numbers of selected patients. The modalities have included home and in-
center hemodialysis delivered four to seven times per week with 
standard blood and dialysate flow rates.  Some centers have employed a 
day time therapy of shorter duration per dialysis session than with the 
thrice weekly schedule. Alternatively, in the nocturnal version, lower 
than standard flow rates have been used but for longer periods of time 
than the usual, often 8 hours per night.  The results of these 
approaches to increased frequency have been reportedly good. Reductions 
in blood pressure, serum phosphate levels and erythropoietin 
requirements have been noted. Improved patient well being has also been 
reported. However, these observations derive from small groups of 
selected patients in a few centers. 

Large numbers of subjects (N = 1,000 or more) are generally required to 
assess the effect of any change in ESRD therapy on mortality and 
cardiovascular events, e.g. stroke, myocardial infarction and heart 
failure, all of which often complicate ESRD. Based on previous studies 
of small numbers of daily dialysis patients, and the uncertain ability 
to randomize patients into daily versus conventional frequency, the 
trials conducted under this RFA will focus on intermediate outcomes.  
These outcomes include blood pressure, LVH, nutritional status, anemia 
quality of life, and vascular access.    

B. Research Goals and Scope

The goal of this research initiative is to establish two clinical 
centers  to conduct a trial of more frequent hemodialysis. It is the 
intent of this solicitation to invite applications from investigators 
who wish to apply their expertise to the testing of more frequent 
hemodialysis. This RFA solicits applications from investigators 
proposing to serve as a Coordinating Clinical Center or a Data and 
Analysis Coordinating Center to develop and conduct such a trial.  

It is anticipated that the studies to be conducted by this consortium 
in this RFA will take place in two CCCs over a period of four years.  
It is envisioned that each CCC will need to enroll a total of between 
150 and 200 patients on dialysis. As stated above, the CCCs may chose 
to work out cooperative arrangements with a network of dialysis 
providers in order to reach enrollment goals. The data collection 
activities of the CCCs will be supported by a single DACC.

C.  Study Design

Applicants for both the CCC and the DACC should respond with research 
protocols involving clinical trials to address the objectives of the 
study and to reach the study goals described in this RFA, and include 
detailed plans regarding their participation in clinical trials. 
Applicants should outline the rationale and background of the proposed 
study, study design and protocols, eligibility and exclusion criteria, 
and type of patients to be included in the protocols, and baseline and 
outcome measures to be assessed, in their applications.  For each of 
the clinical protocols, the CCC applicants should discuss the 
characteristics and number of potential participants that would be 
available from their own geographic region.  Provision of recruitment 
data regarding previous studies in patients with ESRD is required.

Study Phases

The program will be carried out in three phases over a four-year 
period.

Phase I  (Months 1-12):  Protocol Development.  

Work to be performed during this phase includes the development of the 
interventional protocols, including procedures and forms for data 
collection, by the Steering and Planning Committee (see Cooperative 
Agreement Terms and Conditions of Award). A manual of operations 
including well-defined procedures for the studies and for the training 
and certification of clinical personnel in study procedures will be 
written.  Parameters to be assessed in Central Laboratories will be 
outlined. The Data and Analysis Coordinating Center will begin computer 
programming to establish the database for the study.  The collaborative 
protocols for the trials will be developed by the Steering Committee.  
Prior to implementation of the trials, the protocols and manual of 
operations will be reviewed, and must be approved by the External 
Advisory Committee (see Cooperative Agreement Terms and Conditions of 
Award).  The study will move into operational phase (Phase II) only 
with the concurrence of the External Advisory Committee and the NIDDK.  
During this phase outlay of funds will be primarily for appropriate 
levels of salary support for investigators to develop the trial 
protocol(s) and manual of operations, and for travel to the Steering 
and Planning Committee meetings.

Phase II (Months 13-36):  Recruitment of Study Participants/Initiation 
of Interventional Trials
 
At the beginning of this period, training of study staff will begin, to 
ensure uniform protocols and provide certification for study 
procedures.  Over this period potentially eligible participants will be 
identified, invited to the CCCs for baseline assessment, and those 
found eligible will be asked to enter the appropriate trial. During 
this phase the full component of personnel will be included in the 
budget.  Concurrent with recruitment, follow-up of all study 
participants will be conducted in a standardized fashion over regular 
intervals.  The External Advisory Committee will review the progress of 
recruitment at 6 month intervals, review interim outcomes and recommend 
to the NIDDK whether the trial(s) should continue.  The major activity 
during the first half of this phase will be the recruitment, 
assessment, enrollment and retention of patients in the trials.  
Manuscripts describing recruitment of the subjects, and baseline 
demographic and clinical characteristics of the participants will be 
prepared.  Follow-up and data collection on study participants will 
continue throughout this phase, as determined by the study protocols.  
Manuscripts will be prepared and submitted for publication on the 
interim findings from the study.  The last follow-up visit of study 
participants will be scheduled during the final two months of this 
phase.
 
Phase III (Months 37-48):  Final Data Analysis and Close-out of the 
CCCs and the DACC.  

During the final twelve months of the program, the activities include 
final data analyses and preparation of manuscripts on the findings from 
the trials. The Coordinating Clinical Centers, the Data and Analysis 
Coordinating Center, and all central facilities will be closed-out in 
the last two months of this phase of the study. 

Study Organization

The Study organization will include Coordinating Clinical Centers, a 
Data and Analysis Coordinating Center, a Steering and Planning 
Committee, and an External Advisory Committee (see descriptions under 
Cooperative Agreement Terms and Conditions of Award).

MECHANISM OF SUPPORT
 
This RFA will use the NIH U01 award mechanism(s).  As an applicant you 
will be solely responsible for planning, directing, and executing the 
proposed project.  This RFA uses just-in-time concepts.  

The NIH (U01) is a cooperative agreement award mechanism in which the 
Principal Investigator retains the primary responsibility and dominant 
role for planning, directing, and executing the proposed project, with 
NIH staff being substantially involved as a partner with the Principal 
Investigator, as described under the section "Cooperative Agreement 
Terms and Conditions of Award"  

The total project period for applications submitted in response to this 
RFA is four years.  The anticipated award date is September 1, 2003.  

FUNDS AVAILABLE
 
The NIDDK plans to make two awards for Coordinating Clinical Centers 
and one award for a Data and Analysis Coordinating Center.  
Approximately $1,000,000 total cost (direct plus facilities and 
administrative costs) is expected to be available during the first year 
of the study and $3,000,000 for each of the remaining three years of 
the study.  It is anticipated that the award for each Coordinating 
Clinical Center will be about $250,000 total cost in year one, 
$1,250,000 total cost in the second and third years, and $1,000,000 
total cost in the fourth year.  The award for the Data and Analysis 
Coordinating Center will be about $500,000 total cost in years one, 
two, and three of the program, and $1,000,000 in the fourth year.  As 
noted in the Purpose section above, payments to the CCCs will be 
dependent, in part, on obtaining enrollment goals.

Although this program is provided for in the financial plans of the 
NIDDK, 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.

To defray the costs of more frequent dialysis, the Centers for Medicare 
and Medicaid Services (CMS) has authorized one additional composite 
rate payment per week for the duration of the trials to cover the 
reasonable costs of the provision of the additional dialysis sessions.  
CMS will also permit additional home dialysis training payments at the 
composite payment rate plus $20 per training session.  Payment would be 
made for each training session incurred for up to 5 weeks.  These 
payments will not be paid through this U01 mechanism but will be paid 
through the normal Medicare payment billing system.  More information 
about dialysis payment levels can be obtained from the persons listed 
in the Inquiries section at the end of this document.

ELIGIBLE INSTITUTIONS
 
You may submit (an) application(s) if your institution has any of the 
following characteristics:

o For-profit or non-profit organizations 
o Public or private institutions, such as universities, colleges, 
hospitals, and laboratories 
o Units of State and local governments
o Eligible agencies of the Federal government  
o Domestic
 
INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS   

Any individual with the skills, knowledge, and resources necessary to 
carry out the proposed research is invited to work with their 
institution to develop an application for support.  Individuals from 
underrepresented racial and ethnic groups as well as individuals with 
disabilities are always encouraged to apply for NIH programs.   

SPECIAL REQUIREMENTS 

Cooperative Agreement Terms and Conditions of Award

The following terms and conditions will be incorporated into the award 
statement and provided to each Principal Investigator as well as to the 
institutional officials at the time of the award.  These terms are in 
addition to, not in lieu of, otherwise applicable Office of Management 
and Budget (OMB) administrative guidelines, HHS Grant Administration 
Regulations at 45 CFR Part 74 and 92, and other HHS and NIH Grants 
Administration policy statements.

The administrative and funding instrument used for this program is the 
cooperative agreement (U01), an "assistance" mechanism (rather than an 
"acquisition" mechanism), in which substantial NIH scientific and/or 
programmatic involvement with awardees is anticipated during the 
performance of the activity.  Under the cooperative agreement, the NIH 
purpose is to support and/or stimulate the recipient's activity by 
involvement in and otherwise working jointly with the award recipient 
in a partner role, but it is not to assume direction, prime 
responsibility, or a dominant role in the activity.  Consistent with 
the cooperative agreement concept, the dominant role and prime 
responsibility for the planned activity reside with the awardees for 
the project as a whole, although specific tasks and activities in 
carrying out the activity will be shared among the awardees and the 
NIDDK Project Scientist.

(1) Awardees' Rights and Responsibilities  

Awardees will have primary responsibility for the project as a whole, 
including protocol development, enrollment of study participants, data 
collection, data quality control, management of the trials, final data 
analyses and interpretation, and preparation of publications.  Awardees 
will retain custody of and have primary rights to their data developed 
under these awards for the duration of the awards, subject to 
Government (e.g., NIDDK, NIH, or PHS) rights or access consistent with 
current HHS and NIH policies.

Coordinating Clinical Centers

The Coordinating Clinical Center investigators will have direct 
responsibility for developing the study protocol(s) and uniform data 
collection forms, identifying potentially eligible study participants, 
assessing their eligibility to participate in the clinical trials, 
conducting baseline and follow-up visits, obtaining blood, urine, and 
other biological samples, performing measures of dialysis delivery and 
other measurements, collecting data (both clinical and cost related), 
and transmitting it in a timely fashion to the Data and Analysis 
Coordinating Center.  They, along with staff from the Data and Analysis 
Coordinating Center, will also be responsible for making presentations 
at scientific meetings and writing and publishing manuscripts on the 
findings of their studies. A CCC will work collaboratively with the 
other CCC and the DACC, and will follow study protocols.

Data and Analysis Coordinating Center

The Data and Analysis Coordinating Center will be responsible for 
assisting the CCC investigators, through the Steering and Planning 
Committee, in developing the trial protocol(s) during Phases I and II.  
The Data and Analysis Coordinating Center will create data collection 
forms based on input from the Steering and Planning Committee. The Data 
and Analysis Coordinating Center will be responsible for establishing a 
database to accommodate data sent by the Coordinating Clinical Centers, 
developing a web-based data communication system, assessing data 
quality and completeness throughout the study, and providing general 
assistance to the Coordinating Clinical Centers to maintain long-term 
participation of the study subjects and their adherence to the study 
protocols.  The Data and Analysis Coordinating Center will also create 
a web site for study information available to the public.

The Data and Analysis Coordinating Center will also perform analyses as 
suggested by the Coordinating Clinical Centers, as well as propose 
original analyses to the collaborative group for their consideration.  
The Data and Analysis Coordinating Center will prepare periodic reports 
on the progress of the study, including data quality control, and 
interim and final results to the Steering and Planning Committee, the 
NIDDK and the External Advisory Committee.

The DACC will be responsible for coordinating transfer of biologic 
samples and, to a repository to be established by the NIDDK. The Data 
and Analysis Coordinating Center will be responsible for arranging 
meetings and conference calls of the Steering and Planning Committee 
and will perform other administrative functions necessary to coordinate 
the efficient operation of the Frequent Hemodialysis Clinical Trial 
Network.  The Data and Analysis Coordinating Center will establish, via 
subcontracts, Central Laboratories and other necessary adjuncts to the 
study, as necessitated by the study protocol(s).  The DACC will be 
expected to provide the NIDDK and CMS with data (both clinical and cost 
related) in a uniform, usable platform throughout the course of the 
studies and after the termination of the studies supported by this RFA.  

(2) NIDDK Staff Responsibilities

The NIDDK will name a Program Director and a Project Scientist to the 
project from within the Division of Kidney, Urologic and Hematologic 
Diseases.  The Program Director will be responsible for the overall 
management of the project and will oversee all operational aspects of 
the project.  The Program Director will assist the Steering and 
Planning Committee in carrying out the study and will serve as 
Executive Secretary of the External Advisory Committee. The Project 
Scientist will have substantial scientific-programmatic involvement in 
assisting protocol development, quality control, interim data analysis, 
final data analysis and interpretation, preparation of publications, 
and will provide assistance in coordination and performance monitoring.  
The NIDDK Project Scientist will have a voting membership on the 
Steering and Planning Committee. The NIDDK reserves the right to 
terminate or curtail the study (or an individual award) in the event of 
difficulties in recruiting participants to the study, maintaining high 
rates of follow-up and data collection/completion of participants' 
tests, in timely data reporting, achieving high levels of data quality, 
maintaining adherence to the study protocol(s), working cooperatively 
or other major breaches of the protocol(s), or human subject or ethical 
issues that may dictate a premature termination. The study will 
progress from one phase to the next only with NIDDK approval. 

(3) Centers for Medicare and Medicaid Services (CMS) Staff 
Responsibilities

The CMS will name one project liaison representative to participate in 
these trials and assist the NIDDK in carrying out the study.  The 
liaison representative will have experience in Medicare ESRD program 
and payment policy.  The liaison representative will serve as a voting 
member of the steering and planning committee and will attend meetings 
of the EAC.  The project liaison representative will have substantial 
involvement in the development of cost data collection design, 
collection and analysis. The DACC and CCCs will cooperate with the 
Centers for Medicare and Medicaid Services (CMS) in the design and 
collection of cost data relevant to the provision of daily dialysis.  
This will include the costs of training patients as well as the weekly 
maintenance costs of providing daily dialysis.

(4) Collaborative Responsibilities  

The Steering and Planning Committee, composed of each of the Principal 
Investigators of the CCCs, the Principal Investigator of the DACC, the 
NIDDK Project Scientist, the Chairperson of the Steering and Planning 
Committee, and the CMS liaison representative will be the main 
governing board of the study.  NIDDK may supplement the Steering and 
Planning Committee with experts in the fields of nephrology, clinical 
trials, and statistics as deemed necessary.  This committee will have 
the primary responsibility for developing the study protocol(s), 
facilitating the conduct of participant follow-up and testing, 
monitoring completeness of data collection adherence to protocol(s), 
and timely transmission to the Data and Analysis Coordinating Center, 
and reporting the study results.  It will also be responsible for 
establishing study policies in such areas as access to patient data and 
specimens, ancillary studies, publications and presentations, and 
performance standards.

Each member of the Steering and Planning Committee will have one vote, 
and all major scientific decisions will be determined by a majority 
vote of the Steering and Planning Committee.  A Chairperson will be 
chosen by the NIDDK from among the Steering and Planning Committee 
members (but not one of the NIDDK or CMS representatives).
 
An independent External Advisory Committee (EAC), selected by the 
Director, NIDDK, will review periodically the progress of the study to 
ensure patient safety during the conduct of the trial(s).  This group 
will include experts in the relevant medical, epidemiological, 
radiological, statistical, and ethics fields, as well as lay 
representatives, who are not otherwise involved in the study.  The EAC 
will review the study protocol(s) as developed during Phases I and II, 
and evaluate results, monitor data quality, participant safety, and 
provide operational and policy advice to the Steering and Planning 
Committee and to the NIDDK regarding the status of the study.  One of 
the NIDDK representatives will serve as Executive Secretary of the 
External Advisory Committee.  The members of the EAC will review the 
trials' progress and report to the NIDDK at least once each year, or 
more often if necessary. 

(5) Arbitration

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

WHERE TO SEND INQUIRIES

We encourage inquiries concerning this RFA and welcome the opportunity 
to answer questions from potential applicants.  Inquiries may fall into 
three areas:  scientific/research, peer review, and financial or grants 
management issues:

o Direct your questions about scientific/research issues to:

Paul Eggers, Ph.D, 
Division of Kidney, Urologic, and Hematologic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Boulevard, Room 617 MSC 5458
Bethesda, Maryland 20892-5458 
(for express or courier service use 20817)
Telephone:  (301) 594-7717
FAX:  (301) 480-3510 
Email:  pe39h@nih.gov

Thomas Hostetter, M.D.
Division of Kidney, Urologic, and Hematologic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Boulevard, Room 647 MSC 5458
Bethesda, Maryland 20892-5458 
(for express or courier service use 20817)
Telephone:  (301) 594-8864
FAX:  (301) 480-3510 
Email:  th192u@nih.gov

o Direct your questions about peer review issues to:

Francisco O. Calvo, Ph.D.
Chief, Review Branch
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Boulevard, Room 752 MSC 5452
Bethesda, MD  20892
Telephone:  (301) 594-8897
FAX:  (301) 480-3505
Email: fc15y@nih.gov

o Direct your questions about financial or grants management matters 
to:

Ms. Helen Ling
Senior Grants Management Specialist
Grants Management Branch
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Blvd., Room 732
MSC 5456
Bethesda, MD  20892-5456
(For Express Mail Use Zip Code 20817)
Telephone:  (301) 594-8857
Fax: (301) 480-3504
Email: hl12d@nih.gov 
 
LETTER OF INTENT
 
Prospective applicants are asked to submit a letter of intent that 
includes the following information:

o Descriptive title of the proposed research
o Name, address, and telephone number of the Principal Investigator
o Names of other key personnel 
o Participating institutions
o Number and title of this RFA 

Although a letter of intent is not required, is not binding, and does 
not enter into the review of a subsequent application, the information 
that it contains allows IC staff to estimate the potential review 
workload and plan the review.
 
The letter of intent is to be sent by the date listed at the beginning 
of this document.  The letter of intent should be sent to:

Francisco O. Calvo, Ph.D.
Chief, Review Branch
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Boulevard, Room 752 MSC 5452
Bethesda, MD  20892
(Courier use ZIP 20817)
Telephone:  (301) 594-8897
FAX:  (301) 480-3505
Email: fc15y@nih.gov

SUBMITTING AN APPLICATION

Applications must be prepared using the PHS 398 research grant 
application instructions and forms (rev. 5/2001).  The PHS 398 is 
available at http://grants.nih.gov/grants/funding/phs398/phs398.html in 
an interactive format.  For further assistance contact GrantsInfo, 
Telephone (301) 435-0714, Email: GrantsInfo@nih.gov.
 
USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 
5/2001) application form must be affixed to the bottom of the face page 
of the application.  Type the RFA number on the label.  Failure to use 
this label could result in delayed processing of the application such 
that it may not reach the review committee in time for review.  In 
addition, the RFA title and number must be typed on line 2 of the face 
page of the application form and the YES box must be marked. The RFA 
label is also available at: 
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf.
 
SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten 
original of the application, including the Checklist, and three signed, 
photocopies, in one package to:
 
Center For Scientific Review
National Institutes Of Health
6701 Rockledge Drive, Room 1040, MSC 7710
Bethesda, MD  20892-7710
Bethesda, MD  20817 (for express/courier service)
 
At the time of submission, two additional copies of the application and 
any appendices must be sent to:

Francisco O. Calvo, Ph.D.
Chief, Review Branch
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Boulevard, Room 752 MSC 5452
Bethesda, MD  20892
(Courier use ZIP 20817)
Telephone:  (301) 594-8897
FAX:  (301) 480-3505
Email: fc15y@nih.gov
 
APPLICATION PROCESSING: Applications must be received by the 
application receipt date listed in the heading of this RFA.  If an 
application is received after that date, it will be returned to the 
applicant without review.
 
The Center for Scientific Review (CSR) will not accept any application 
in response to this RFA that is essentially the same as one currently 
pending initial review, unless the applicant withdraws the pending 
application.  The CSR will not accept any application that is 
essentially the same as one already reviewed. This does not preclude 
the submission of substantial revisions of applications already 
reviewed, but such applications must include an Introduction addressing 
the previous critique.

PEER REVIEW PROCESS  
 
Upon receipt, applications will be reviewed for completeness by the CSR 
and responsiveness by the NIDDK. 

Incomplete applications will be returned to the applicant without 
further consideration.  And, if the application is not responsive to 
the RFA, CSR staff may contact the applicant to determine whether to 
return the application to the applicant or submit it for review in 
competition with unsolicited applications at the next appropriate NIH 
review cycle.

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 NIDDK in accordance with the review 
criteria stated below.  As part of the initial merit review, all 
applications will:

o Receive a written critique
o Undergo a process in which only those applications deemed to have the 
highest scientific merit, generally the top half of the applications 
under review, will be discussed and assigned a priority score
o Receive a second level review by the National Diabetes and Digestive 
and Kidney Diseases Advisory Council.
 
REVIEW CRITERIA

    REVIEW CRITERIA FOR COORDINATING CLINICAL CENTERS

    General: The ability to regionally recruit sufficient numbers of 
subjects for randomization, to provide the proposed frequent 
hemodialysis therapy, to provide cost data, and to document adherence 
to the protocol in a large number of dialysis sites will be key review 
criteria.

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

    Approach:  Does the applicant propose sound approaches to achieve the 
aims of the RFA? Is the potential pool of study participants available 
to the investigator outlined clearly?  Have realistic estimates been 
made regarding the number of participants who will prove to be eligible 
for the studies?  Among persons found eligible during screening, have 
realistic participation rates been applied to meet the sample size 
goals stated in the RFA?  Has the racial, ethnic, and gender 
composition of the proposed study participants been adequately 
described, and plans described for appropriate analyses?  What plans 
have been presented to ensure the high rates of follow-up and high 
rates of adherence mandated by the study protocol? What steps are 
planned for data quality control?  The applicant must provide plans to 
ensure the complete, reliable, and timely transmission of study data to 
the Data and Analysis Coordinating Center.  Knowledge of the possible 
problems associated with the conduct of clinical trials  and any 
potential issues of importance in this study should be described.

    Investigators:  Is the Principal 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 other 
researchers?  Are the Principal Investigator and her/his co-
investigators experienced in collaborating with other investigators in 
a multi-center study?  Are the investigators willing to participate in 
establishing and conducting a common protocol?  Does the Principal 
Investigator and the proposed study team possess experience in 
recruiting participants to pilot and feasibility studies and to long-
term interventional studies?  Does the Principal Investigator and the 
proposed study team possess experience in clinical trial design to 
ensure meaningful participation in design of the trial? 

    Staff Qualifications:  Documented specific competence and relevant 
experience of professional, technical, and administrative staff 
pertinent to the operation of a Coordinating Clinical Center are 
required.  Documented experience in nephrology, and specifically in the 
field of ESRD and clinical trial methodology is required.  

    Environment:  Does the scientific environment in which the work will be 
done contribute to the probability of success?  Documented adequacy of 
the proposed facility and space is necessary.  Is there evidence of 
institutional support and commitment for the proposed program? 

    Access to Large Number of Eligible Patients and Ability to Recruit 
Large Numbers of Patients in Clinical Trials:  Evidence of the ability 
to access sufficient numbers of appropriate patients from which 
potential study participants will be recruited is necessary.  
Documentation must be provided on the ability to contact patients 
identified in order to invite them to more detailed, clinical 
assessments of their eligibility to participate in the trial(s). 
Provisions must be made to ensure subject confidentiality and ethical 
standards.  

    REVIEW CRITERIA FOR A DATA AND ANALYSIS COORDINATING CENTER:

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

    Approach: Does the applicant acknowledge potential problem areas and 
consider alternative tactics in the implementation and performance of 
the trials necessary to achieve the goals of this RFA?  What is the 
approach to handle missing follow-up data and patient non-adherence?  
How does the applicant propose to collect and analyze dialysis cost 
data?  Experience in developing protocols, developing web-based 
technology for data collection, establishing and maintaining large 
databases for data from the Coordinating Clinical Centers, plans for 
analysis of the combined data, and efforts to ensure high quality data 
collection, and ensuring study participant adherence and 
confidentiality will be evaluated. 

    Investigators:  Is the Principal 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 other 
researchers?  Are the Principal Investigator and her/his co-
investigators experienced in collaborating with other investigators in 
a multi-center study?  Documented experience in epidemiology, clinical 
trial methodology and biostatistics is required.  Does the applicant 
have expertise in longitudinal data analysis?  The level of expertise 
of consultants in nephrology will be considered.  Experience in 
database development, data management, and statistical analysis is 
required.  The ability of the investigators from the Data and Analysis 
Coordinating Center to take the lead in developing a cooperative 
relationship among the Coordinating Clinical Centers and the Central 
Laboratories, and to exercise appropriate leadership in matters of 
study design, data acquisition, data management, data quality, data 
analysis, repository function, and administration and coordination of 
Steering and Planning Committee meetings will be considered.

    Environment:  Does the scientific environment in which the work will be 
done contribute to the probability of success?  Documented adequacy of 
the proposed facility and space is necessary.  Is there evidence of 
institutional support and commitment for the proposed program? 

	ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, your 
application will also be reviewed with respect to the following:

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

o INCLUSION:  The adequacy of plans to include subjects from both 
genders, all racial and ethnic groups (and subgroups), and children as 
appropriate for the scientific goals of the research.  Plans for the 
recruitment and retention of subjects will also be evaluated. (See 
Inclusion Criteria included in the section on Federal Citations, below)

o DATA SHARING:  The adequacy of the proposed plan to share data. 

o BUDGET:  The reasonableness of the proposed budget and the requested 
period of support in relation to the proposed research.

RECEIPT AND REVIEW SCHEDULE

Letter of Intent Receipt Date:  February 14, 2003
Application Receipt Date:  March 14, 2003
Peer Review Date:  June/July 2003
Council Review:  September 2003
Earliest Anticipated Start Date:  September 30, 2003

AWARD CRITERIA

Award criteria that will be used to make award decisions include:

o Scientific merit (as determined by peer review)
o Availability of funds
o Programmatic priorities.
 
REQUIRED FEDERAL CITATIONS 

MONITORING PLAN AND DATA SAFETY AND MONITORING BOARD:
Research components involving Phase I and II clinical trials must 
include provisions for assessment of patient eligibility and status, 
rigorous data management, quality assurance, and auditing procedures.  
In addition, it is NIH policy that all clinical trials require data and 
safety monitoring, with the method and degree of monitoring being 
commensurate with the risks (NIH Policy for Data Safety and Monitoring, 
NIH Guide for Grants and Contracts, June 12, 1998: 
http://grants.nih.gov/grants/guide/notice-files/not98-084.html).  

INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: 
It is the policy of the NIH that women and members of minority groups 
and their sub-populations must be included in all NIH-supported 
clinical research projects unless a clear and compelling justification 
is provided indicating that inclusion is inappropriate with respect to 
the health of the subjects or the purpose of the research. This policy 
results from the NIH Revitalization Act of 1993 (Section 492B of Public 
Law 103-43).

All investigators proposing clinical research should read the AMENDMENT 
"NIH Guidelines for Inclusion of Women and Minorities as Subjects in 
Clinical Research - Amended, October, 2001," published in the NIH Guide 
for Grants and Contracts on October 9, 2001 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a 
complete copy of the updated Guidelines are available at 
http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm.
The amended policy incorporates: the use of an NIH definition 
of clinical research; updated racial and ethnic categories in 
compliance with the new OMB standards; clarification of language 
governing NIH-defined Phase III clinical trials consistent with the new 
PHS Form 398; and updated roles and responsibilities of NIH staff and 
the extramural community.  The policy continues to require for all NIH-
defined Phase III clinical trials that: a) all applications or 
proposals and/or protocols must provide a description of plans to 
conduct analyses, as appropriate, to address differences by sex/gender 
and/or racial/ethnic groups, including subgroups if applicable; and b) 
investigators must report annual accrual and progress in conducting 
analyses, as appropriate, by sex/gender and/or racial/ethnic group 
differences.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN 
SUBJECTS:  The NIH maintains a policy 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 is available at 
http://grants.nih.gov/grants/funding/children/children.htm. 

REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS:  
NIH policy requires education on the protection of human subject 
participants for all investigators submitting NIH proposals for 
research involving human subjects.  You will find this policy 
announcement in the NIH Guide for Grants and Contracts Announcement, 
dated June 5, 2000, at
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: 
The Office of Management and Budget (OMB) Circular A-110 has been 
revised to provide public access to research data through the Freedom 
of Information Act (FOIA) under some circumstances.  Data that are (1) 
first produced in a project that is supported in whole or in part with 
Federal funds and (2) cited publicly and officially by a Federal agency 
in support of an action that has the force and effect of law (i.e., a 
regulation) may be accessed through FOIA.  It is important for 
applicants to understand the basic scope of this amendment.  NIH has 
provided guidance at 
http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm.

Applicants may wish to place data collected under this RFA in a public 
archive, which can provide protections for the data and manage the 
distribution for an indefinite period of time.  If so, the application 
should include a description of the archiving plan in the study design 
and include information about this in the budget justification section 
of the application. In addition, applicants should think about how to 
structure informed consent statements and other human subjects 
procedures given the potential for wider use of data collected under 
this award.

URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and 
proposals for NIH funding must be self-contained within specified page 
limitations. Unless otherwise specified in an NIH solicitation, 
Internet addresses (URLs) should not be used to provide information 
necessary to the review because reviewers are under no obligation to 
view the Internet sites.   Furthermore, we caution reviewers that their 
anonymity may be compromised when they directly access an Internet 
site.

HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to 
achieving the health promotion and disease prevention objectives of 
"Healthy People 2010," a PHS-led national activity for setting priority 
areas. This RFA is related to one or more of the priority areas. 
Potential applicants may obtain a copy of "Healthy People 2010" at 
http://www.health.gov/healthypeople.

AUTHORITY AND REGULATIONS: This program is described in the Catalog of 
Federal Domestic Assistance No. 93.849 and is not subject to the 
intergovernmental review requirements of Executive Order 12372 or 
Health Systems Agency review.  Awards are made under authorization of 
Sections 301 and 405 of the Public Health Service Act as amended (42 
USC 241 and 284) and administered under NIH grants policies described 
at http://grants.nih.gov/grants/policy/policy.htm and under Federal 
Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. 

The PHS strongly encourages all grant recipients to provide a smoke-
free workplace and discourage the use of all tobacco products.  In 
addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits 
smoking in certain facilities (or in some cases, any portion of a 
facility) in which regular or routine education, library, day care, 
health care, or early childhood development services are provided to 
children.  This is consistent with the PHS mission to protect and 
advance the physical and mental health of the American people.

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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