MTOPS PROSTATE SAMPLES ANALYSIS CONSORTIUM (MPSA)

Release Date:  November 21, 2001

RFA:  RFA-DK-02-017

National Institute of Diabetes and Digestive and Kidney Diseases
 (http://www.niddk.nih.gov)

National Institute on Aging
 (http://www.nia.nih.gov)

Letter of Intent Receipt Date:  February 20, 2002
Application Receipt Date:       March 20, 2002

PURPOSE

The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) 
and the National Institute on Aging (NIA) invite cooperative agreement 
applications to establish a MTOPS Prostate Samples Analysis Consortium (MPSA) 
that will participate in the discovery and validation of biologic markers or 
genetic susceptibility tests for the detection, risk assessment, and 
assessment of disease progression of benign prostatic hyperplasia (BPH). The 
NIDDK has sponsored a large clinical trial, entitled "Medical Therapy of 
Prostatic Symptoms" or MTOPS, of two treatments for BPH, finasteride and 
doxazosin. Serum samples were collected yearly from the participants, one 
quarter of the participants had prostate biopsies collected in years 0, 1, 
and 5 of the trial. These samples will allow the evaluation of potential 
biomarkers or genetic susceptibility tests for BPH, response to 
pharmacological treatments for BPH, and/or correlation with clinical 
parameters. The purpose of the MTOPS Prostate Samples Analysis (MPSA) 
Consortium is to establish a scientific consortium of investigators with 
resources for basic and translational research on biomarkers for BPH. The 
existing MTOPS Data Coordinating Center will be an integral member of this 
new MPSA Consortium.

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic for-profit and non-profit 
organizations, public and private institutions such as universities, 
colleges, hospitals, laboratories, units of State and local governments, and 
eligible agencies of the Federal government. Foreign institutions are not 
eligible to apply. Racial/ethnic minority individuals, women, and persons 
with disabilities are encouraged to apply as Principal Investigators.

MECHANISM OF SUPPORT

This RFA will use the NIH Cooperative Research (U01) Award mechanism, an  
"assistance" mechanism (rather than "acquisition" mechanism) in which 
substantial NIH scientific and/or programmatic involvement with the awardee 
is anticipated during the performance of the activity.  Under the cooperative 
agreement, the NIH purpose is to support and stimulate the recipient"s 
activity by involvement in, and otherwise working jointly with, the award 
recipient in a partner role, but it is not to assume direction, prime 
responsibility, or a dominant role in the activity. Consistent with this 
concept, the dominant role and prime responsibility for the activity resides 
with the awardees for the project as a whole, although specific tasks and 
activities in carrying out the research will be shared among the awardees and 
the NIH Project Scientists. Details of the responsibilities, relationships, 
and governance of a study funded under a cooperative agreement are discussed 
later in this document under the section "TERMS AND CONDITIONS OF AWARD FOR 
THE MPSA CONSORTIUM."

This RFA is a one-time solicitation. The total project period for an 
application submitted in response to this RFA may not exceed 3 years. The 
anticipated award date is September 30, 2002.

FUNDS AVAILABLE

The NIDDK intends to commit approximately $3,000,000 in total costs in FY 
2002 to fund approximately four to five Biomarker Units and one Pathology 
Coordination Center. The NIA plans to commit $500,000 in total costs for high 
quality research pertinent to the NIA mission, subject to the availability of 
funds. An applicant for a Biomarker Unit may request a project period of up 
to three years and budget for direct costs of up to $300,000 per year. Should 
an applicant plan to include subcontracts to other institutions or 
organizations, only the direct costs of those subcontracts will be used to 
tally the total costs that apply toward the $300,000 direct cost cap. An 
applicant for a Pathology Coordinating Center may request a project period of 
up to three years and budget for direct costs of up to $500,000 per year. For 
further budget information, see the section "APPLICATION PROCEDURES." Because 
the nature and scope of research proposed in response to this RFA may vary, 
we anticipate that the size of awards will vary also. Although this program 
is provided for in the financial plans of NIDDK and NIA, awards pursuant to 
this RFA are contingent upon the availability of funds for this purpose and 
the receipt of a sufficient number of applications of outstanding scientific 
and technical merit. At this time, NIDDK and NIA have not determined whether 
or how this solicitation will be continued beyond the present RFA.

RESEARCH OBJECTIVES

Background

Benign prostatic hyperplasia (BPH) affects more than 50% of men past the age 
of 50. BPH is an expensive disease. BPH treatments cost an estimated $5 
billion each year, and as the U.S. population ages, these costs will 
increase. If left untreated, BPH can lead to urinary tract infections, 
urinary retention, and in occasional cases, kidney disease. BPH is a 
heterogeneous disorder, with growth occurring at variable growth rates in 
different portions of the gland and a variable clinical presentation and 
response to therapy. Although there is no clear link between BPH and prostate 
cancer, these two prostate diseases occur in a similar population of aging 
men. NIDDK has sponsored a large clinical trial entitled "Medical Therapy of 
Prostatic Symptoms (MTOPS)" of two treatments for BPH, finasteride, and 
doxazosin. The MTOPS study is nearing completion. This trial included the 
acquisition and storage of serum samples from 4000 patients, and prostate 
biopsies from approximately 900 patients. Serum samples were collected at the 
beginning of the study, and at yearly intervals. Each 3 ml sample was split 
into 6 aliquots, and frozen. Approximately one-quarter of the participants 
had prostate biopsies taken at years 0, 1, and 5. Each sample consisted of 6 
cores, 4 cores were fixed in formalin and imbedded in paraffin. The remaining 
two samples were frozen in OCT embedding material and stored at -70?C. Each 
paraffin and frozen section block has been sectioned at least once to 
establish a pathological diagnosis. The serum and prostate biopsy samples are 
stored currently in a repository at the MTOPS Pathology Coordinating Unit. 
Clinical information for each patient is stored in the MTOPS Data 
Coordinating Center. The pathological diagnoses of these tissue biopsies are 
predominantly chronic prostatitis, simple atrophy, or the various forms of 
hyperplasia (i.e. adenomatous, fibromyoadenomatous, leiomyoma, etc.). The 
availability of these materials presents an extraordinary opportunity to 
develop and evaluate biological and genetic markers that will further our 
understanding of the biological and genetic processes contributing to BPH and 
prostate cancer, or related to response to therapy of BPH. The importance of 
prostate biomarkers has been repeatedly emphasized at national and 
international meetings including the NCI-sponsored Prostate Research Progress 
Group, April 1997, the International Symposium on Prostate Growth, March 
1998, and the Symposium on Prostate Growth and Aging, September 13-15, 2000.

In contrast to rapid progress obtained with PSA for the detection of prostate 
cancer, BPH must be diagnosed clinically by symptoms, clinical exam, and 
diagnostic imaging. There is a great need for better markers for BPH, and for 
genetic tests to identify patients at high risk for early BPH, for rapidly 
progressing BPH, and for prostate cancer.  Genetic tests are also needed to 
determine which patients will respond to various forms of pharmacological 
therapy.  The large number of well-characterized patients in the MTOPS 
consortium should allow for the development and testing of such markers.

Objectives and Scope

The intent of this initiative is to assemble a cross-disciplinary, multi-
institutional MPSA Consortium with a range of expertise to perform 
cooperative studies using the MTOPS material to evaluate genetic, 
immunologic, or biochemical biomarkers relevant to the progression of BPH, 
response to therapy, and the concurrent development of prostate cancer. For 
simplicity, the term "biomarker" below will include genetic, immunologic, or 
biochemical markers of disease or susceptibility to disease. 

The Consortium will generate and validate the biomarkers for use by the 
research community for a variety of investigations, including testing early 
detection, prevention, therapeutics, or imaging strategies, and assure their 
availability to the research community. The approaches used for generating, 
characterizing, and validating the biomarkers will reflect the blend of 
experience and creativity of the Consortium component units and will be 
originated by these investigators. The consortium may also produce research 
tools such as serum protein arrays, layered expression arrays, or tissue 
arrays that can be used by the research community. It is anticipated that one 
Pathology Coordination Center and four or five Biomarker Units will be 
awarded. Each Biomarker unit will consist of a cross-disciplinary team that 
may reside, if appropriate, at several institutions. 

It is expected that either the Principal Investigator or a co-investigator 
will have demonstrated, published experience in basic research studies that 
focus predominantly on BPH utilizing human tissue samples. In addition, 
either the Principal Investigator or a co-investigator must have demonstrated 
expertise in multi-center clinical trials focused on BPH treatment.  One of 
the investigators must demonstrate expertise in translational research 
studies focused on prostate diseases. The MTOPS Data Coordinating Center, 
funded separately from this RFA, will be a part of the MTOPS PSA consortium 
and will perform a follow-up study of the MTOPS participants by 
questionnaires and/or death certificates.

The participating NIH Institutes have briefly outlined broad areas of 
biomedical interest related to the goals of this RFA. The NIDDK"s primary 
interest is in the production and validation of biologic markers or genetic 
susceptibility tests for the detection, risk assessment, and assessment of 
disease progression of BPH.  Since age is a major risk factor for BPH and 
prostate cancer, the NIA is interested in the development of biomarkers 
associated with the aging process and with age-related changes in the 
sensitivity and specificity of developed biomarkers.

The following example illustrates the functions of the MPSA consortium and 
the ability it offers for moving basic research findings into clinical 
practice: 

An investigator within the Consortium identifies a putative biomarker through 
original laboratory research. Based on the pilot research findings on locally 
obtained prostate samples, the putative marker seems to be useful for BPH 
detection or progression or cancer detection. The investigator can then 
approach the Steering Committee for additional evaluation of the marker. The 
Steering Committee then has the responsibility to review the data on the 
potential marker using its standing formal criteria as a guide, which will 
likely include requirements for laboratory tests, quality controls, and 
sample size considerations. If necessary, scientific resources from other 
Biomarker Centers can be pooled to conduct studies. There will also be 
flexibility so that investigators outside the Consortium could form a 
collaboration with one of the existing centers or directly bring their 
discoveries to the Steering Committee (e.g., by Letter of Intent). The 
investigator, in turn, will agree to share his research findings and become 
an associate member of the Consortium.

A. Interactions

The MPSA Consortium, through its component units, Steering Committee, and 
subcommittees will do the following:

o Define how biomarkers will be validated (pathology, imaging, tissue array, 
quantitative RT/PCR, SNPs, etc.),

o Decide when candidate biomarkers have been sufficiently tested against 
local (non-MTOPS) BPH tissue or serum samples, and are ready to be tested 
against MTOPS samples,

o Prioritize the testing of candidate biomarkers against the MTOPS serum and 
prostate biopsy samples,

o Define methods to use MTOPS serum and prostate biopsy samples efficiently. 
For example, the consortium may decide to produce and use tissue arrays, 
moderate throughput ELISA techniques, or batch testing of biomarkers using 
multi-analyte methods,

o Identify technological impediments to generating and validating biomarkers, 
and select strategies to surmount them, 

o Share technological, methodological, and clinical information both between 
MPSA components and with the broader research community, and

o Decide when a candidate biomarker is sufficiently characterized and 
validated so that the biomarker and all available accompanying data can be 
distributed to the research community for individual investigator-initiated 
projects. 

At each step, input will be sought from experts within the MPSA Consortium, 
within other NIH-sponsored consortia (for example, NIDDK Biotechnology 
Centers Consortium [RFA DK-99-002, RFA DK00-009], Prostate and Genitorurinary 
Development [RFA DK-00-015]0, and from the broader research community.

During the course of the funding period, technologies will improve and the 
rate of progress and scope of research under the cooperative agreement may 
change. Principal Investigators, in consultation with the NIH will be 
expected to make necessary adjustments to accommodate the changing research 
environment, to remain focused on appropriate goals, to maintain excellent 
coordination with the other projects funded under this RFA, and to 
incorporate new technological advances.

B. Biomarker Units

Each Unit will be a self-assembled group of multidisciplinary investigators 
from one or more institutions who provide a unique mix of complementary 
research experiences. An applicant team will incorporate an appropriate mix 
of expertise needed to achieve the Unit"s goals and to contribute 
substantially to achieving the overall MPSA Consortium goals. It is expected 
that either the Principal Investigator or a co-investigator will have 
demonstrated, published experience in basic research studies that focus 
predominantly on BPH utilizing human tissue samples. In addition, either the 
Principal Investigator or a co-investigator must have demonstrated expertise 
in multi-center clinical trials focused on BPH treatment. One of the 
investigators must demonstrate expertise in translational research studies 
focused on prostate diseases.   

To expedite translational research, each team must have expertise in both 
biomarker, and the clinical properties of human prostate disease that inform 
the design of early detection strategies, prevention, or therapy. Additional 
areas of expertise may include, but are not limited to, phenotypic, 
genotypic, genomic or proteomic analyses of disease, prostate biology, 
pathology, or pathogenesis, therapy, prevention, early detection, diagnostic, 
laboratory technology or validation, biometry, or epidemiology. The expertise 
in laboratory science is expected to include research in the biology of 
prostate hyperplasia and neoplasia that encompasses the development, 
characterization and testing of biomarkers, development of relevant 
technologies for biomarker detection, and analytical tools for the evaluation 
of biomarkers for detection and risk assessment. The expertise in laboratory 
validation will also include knowledge and practice of Standard Operating 
Procedures and experience in the statistical evaluation of accuracy, 
precision, reproducibility, and performance characteristics of tests in 
multi-center settings. Computational and informatic needs of the Consortium 
will be provided by a MTOPS Data Coordinating Center.

The approaches used to generate, characterize, and validate biomarkers for 
BPH and other prostatic disease will reflect the blend of experience and 
creativity of the component investigators. The following examples are 
intended only to provide broad direction and should be considered 
illustrative, but not restrictive. An individual application might include 
the following:

1. Propose standards for validating biomarkers in BPH and other prostate 
diseases.

2. Review the literature for existing biomarkers or genetic predispositions, 
and discuss any candidate biomarkers susceptibility loci they have already 
generated.

3. Propose to generate biomarkers using local prostate samples. Such methods 
might include genetic, genomic or proteomic techniques such as SNP analysis, 
differential display, representative difference experiments, gene expression 
arrays, 2-D gels, protein chips, MALDI/TOF, phage display, monoclonal 
antibody production, etc. The application should discuss the clinical 
relevance of the proposed biomarker.

4. Propose methods to characterize the candidate biomarkers of BPH and other 
prostate diseases using local samples. This may include physiological, 
pathological, imaging, and genetic, genomic, or proteomic methods. These 
studies might establish and compare the sensitivity, specificity and 
predictive accuracy of biomarkers in a clinical context, including inter-and 
intra-laboratory reproducibility. A number of putative biomarkers exist that 
could be tested. Statistical power calculations should be discussed.

5. Refine assays and optimize technology. To develop accurate early detection 
screening tests, it is crucial to develop high-throughput assays/technologies 
that are reproducible and cost-effective. The Biomarker Units are expected to 
plan, design, and conduct analytic validation studies, as directed by the 
Steering Committee, for assay procedures and protocols, etc. Validation 
studies might include optimizing the selection of targets, design of internal 
controls, controls for contamination, reagent and instrument standards, 
technical reproducibility, precision and sensitivity, and well-characterized 
panels of reference reagents. 

6. Propose methods to extensively validate the candidate biomarker using the 
MTOPS serum and prostate samples. The amount of sample needed and the 
statistical power calculations should be discussed. These studies might

a) Evaluate the specificity, sensitivity, and diagnostic accuracy of 
biomarkers in predicting extent or severity of disease,

b) Relate biomarker expression to clinical outcome. Correlating these 
biomarkers with the natural history and clinical outcome may prove valuable 
for therapeutic and follow-up strategies,

c) Evaluate computational methods for combining multiple biomarkers for 
earlier detection and risk assessment in clinical settings,

d) Identify high-risk populations and performing comprehensive studies in 
targeted high-risk populations for validation and potential integration of 
novel detection strategies, and 

e) Evaluate gene-environmental interactions for understanding risk and 
variations (polymorphisms) in susceptibility in high-risk cohorts.

7. Indicate how the biomarkers could be used to test early detection, 
therapeutic, prevention, and imaging strategies. 

In the application, applicants must provide methods to maintain unit records, 
establish, standardize, document, and distribute protocols, and provide for 
quality control and budgetary oversight. Each Biomarker Unit will establish a 
database to store, organize, analyze, or visualize data, and to facilitate 
dissemination of information and data-sharing within the Consortium. 
Applicants must also provide methods to oversee the daily operation of their 
unit that will also establish priorities among local candidate biomarkers.

It is anticipated that some of the proposals will be quite speculative and 
innovative, and that applications may lack preliminary data on biomarkers. 
However, applications should include sufficient information to indicate that 
the investigative team has sufficient expertise with proposed techniques and 
that the proposed projects are feasible.

C. Pathology Coordination Center

The Pathology Coordination Center will maintain the MTOPS serum and prostate 
samples. The MTOPS samples are currently housed at the University of 
Colorado. The application must include plans to move the samples, if 
necessary to their own site.

The Pathology Coordination Center will read the prostate biopsies, and 
distribute the MTOPS serum and prostate samples to members of the consortium. 
The Consortium may decide to generate specialized sample sets, including, 
protein arrays or layered expression arrays containing arrayed serum samples, 
or tissue arrays. The Center may also propose to produce and distribute cDNA 
or protein samples obtained by Laser Capture Microdissection. These research 
resources will be made available to the Biomarker Units and, after discussion 
by the Steering Committee, to the wider research community. The applicant 
should discuss in detail how it will generate these specialized reagents and 
how it will handle multiple requests for the samples.

The Pathology Coordination Center should have the ability to scale-up assays 
to allow testing in large number of samples, under the guidance of the 
steering committee. Whereas the Biomarker Units will have responsibility for 
standardizing laboratory assays and developing quality control for reagents 
and technologies, the Pathology Coordination Center should have knowledge and 
practical experience with Standard Operating Procedures and in the evaluation 
of the accuracy, precision, reproducibility, and performance characteristics, 
for example, sensitivity, specificity, positive and negative predictive 
values. These characteristics are important when sampling body fluids or 
mixed cell types where only a very small percentage of cells may exhibit the 
specific genetic or molecular changes.

The Pathology Coordination Center will also provide travel and meeting 
support for the Steering Committee and other committees of the MPSA 
Consortium (see the section "SPECIAL REQUIREMENTS"). 

D. Interactions with the Existing MTOPS Data Coordinating Center.

The MTOPS Data Coordinating Center will maintain the database that contains 
clinical and laboratory data on patients enrolled in the MTOPS study. The 
MTOPS Data Coordinating Center will also perform a follow-up study of the 
MTOPS participants by questionnaire and/or death certificates.

The MTOPS Data Coordinating Center will establish and maintain the Internet-
based mechanism for rapid data and document transmission and electronic 
communication among participants in the MPSA Consortium and between the MPSA 
Consortium and the NIH. These databases and websites will serve the needs of 
all Units established by this initiative and will be an important interface 
between the MPSA Consortium and the larger research community.

E. Data Sharing

Each MPSA Consortium member will obtain data from the MTOPS Data Coordinating 
Center and samples from the Pathology Coordination Center after approval by 
the Steering Committee. Applicants should request support for data retrieval, 
sample retrieval, and biomarker assays in their budgets. For collaborative 
studies and specific data analyses, the Steering Committee will select a 
Statistical Coordinator from among the member institutions. The results of 
those analyses will be delivered to the Steering Committee, which will 
determine (1) if and what further analyses should be performed, (2) how the 
results are interpreted, (3) whether the results impact ongoing data 
collection, ongoing studies, or future studies, and (4) how the findings 
should be disseminated. 

The awardees will retain custody of, and have primary rights to, all data 
developed under these awards, subject to Government rights of access 
consistent with HHS, PHS, and NIH policies.

Restricted availability of unique research resources, upon which further 
studies are dependent, can impede the advancement of research and delivery of 
medical care. Sharing biomaterials, data, and software in a timely manner has 
been an essential element in the rapid progress that has been made in the 
genetic analyses of mammalian genomes. NIH policy requires that investigators 
make unique research resources readily available for research purposes to 
qualified individuals within the scientific community after publication (NIH 
Grants Policy Statement [http://grants.nih.gov/grants/policy/nihgps], 
Principles and Guidelines for Recipients of NIH Research Grants and Contracts 
on Obtaining and Disseminating Biomedical Research Resources: Final Notice, 
December 1999 http://www.nih.gov/od/ott/RTguide_final.htm.
Biomarkers or genetic tests and other research resources that can be patented 
(e.g., tissue arrays, genetic and phenotypic data for human samples) and that 
are produced in projects funded by this RFA are expected to be made available 
and distributed to the broader scientific community.

The NIH is interested in ensuring that research resources developed through 
this RFA become readily available to the research community for further 
research, development, and application, with the expectation that sharing 
will lead to products and knowledge to benefit the public. For this reason, 
NIH is concerned that patents on biomarkers, genetic tests, tissue arrays, 
and phenotypic and genetic data and other research resources might have a 
chilling effect on the future development of products and information that 
may improve the public health. At the same time, NIH recognizes the rights of 
grantees to elect and retain title to subject inventions developed with 
Federal funding under the provisions of the Bayh-Dole Act.

F. Steering and Other Committees 

The Principal Investigator and another senior investigator must be willing to 
be part of a Steering Committee (See TERMS AND CONDITIONS FOR MPSA 
CONSORTIUM) that will be the main governing board of the MPSA Consortium. The 
Steering Committee will meet twice each year, and may form other 
subcommittees (e.g., subcommittees on diseases  [BPH, prostate cancer], 
biomarker validation, phenotyping, bioinformatics, and technology) that will 
meet either in person or by telephone conference calls. A major goal of these 
meetings is to facilitate progress by providing a forum for sharing skills, 
ideas, technology, data, and biological reagents. Participants will also 
discuss quality assurance, bioinformatics, coordination, and training. 

SPECIAL REQUIREMENTS

The RFA has two special requirements regarding research resources produced in 
proposed projects (see APPLICATION PROCEDURES for more information):

o Applications are required to include a specific plan describing how they 
will share with the wider scientific community research resources as well as 
copies of all Material Transfer Agreements used by all institutions involved 
in the applications.  

o A proposed plan addressing if, or how, the PI and grantee institution will 
exercise their intellectual property rights regarding patentable research 
resources, such as biomarkers and phenotypic and genetic data, for all human 
samples produced in projects funded under this RFA. Applicants are encouraged 
to discuss proposals for addressing these requirements with their 
institutional offices of technology transfer.

TERMS AND CONDITIONS OF AWARD FOR THE MPSA CONSORTIUM

The following terms and conditions will be incorporated into the award 
statement and provided to the Principal Investigator(s) and to the 
institutional official at the time of award. These special Terms of Award are 
in addition to and not in lieu of otherwise applicable OMB administrative 
guidelines, HHS Grant Administration Regulations at 45 CFR Parts 74 and 92, 
and other HHS, PHS, and NIH Grant Administration policy statements.

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

1. Awardee Rights and Responsibilities

Common responsibilities
o The PI will have primary authority and responsibility to define objectives 
and approaches and to plan, conduct, analyze, and publish results, 
interpretations, and conclusions of studies conducted under the terms and 
conditions of the cooperative agreement award.

o The PI will assume responsibility and accountability to the applicant 
organization officials and to the NIH Institutes for the performance and 
proper conduct of the research supported by the project in accordance with 
the terms and conditions of the award.

o The PI and another senior investigator will serve as voting members of the 
Steering Committee, and they will attend two Steering Committee meetings a 
year. Each Steering Committee member will be responsible for participating in 
all other Steering Committee activities, for example, conference calls, 
special subcommittee meetings as may be necessary.

o The PI will be responsible for accepting and implementing the goals, 
priorities, procedures, protocols, and policies agreed upon by the Steering 
Committee. Studies will proceed into the implementation stage only with the 
concurrence of the Steering Committee. 

o The PI will be responsible for close coordination and cooperation with the 
other components of the MPSA Consortium and NIH Project Scientists.
	
o The PI will establish an Internal Advisory Committee to provide scientific 
and administrative oversight. The Internal Advisory Committee will be 
composed of the lead center personnel, and other technical or research 
personnel. These individuals are not limited to the Unit faculty. The 
committee is expected to meet at least every two months. The Internal 
Advisory Committee is charged with both prioritizing projects and 
periodically reviewing Unit activities to ensure that the objectives outlined 
in the application are being met.

o Awardees will retain custody of, and have primary rights to, the data 
developed under these awards, subject to Government rights of access 
consistent with current PHS and NIH policies. Investigators conducting 
biomedical research frequently develop unique research resources. However, 
all awardees must adhere to PHS policy for the distribution of unique 
research awards produced with PHS funding as described under Special 
Requirements. The NIH Project Scientists, on behalf of the NIH, will have the 
same access, privileges, and responsibilities regarding the collaborative 
data as all other members of the Steering Committee.

o Within the first three months of the award period, the PI will have the 
responsibility for establishing written milestones.

o Early publication of major findings is encouraged. Publications and oral 
presentations of work performed under this agreement will require appropriate 
acknowledgment of NIH support. Analyses to be performed using the collective 
data from the MPSA Consortium institutions will be determined and directed by 
the Steering Committee. Individual components wishing to perform analyses of 
local data will inform the Steering Committee of any such analyses prior to 
initiation in order to avoid duplication. Review and approval by the Steering 
Committee, or a Publications Subcommittee, will be required for all analyses 
before publication or presentation according to criteria that will be 
developed by the Steering Committee. 

o Effective conduct of the MPSA Consortium goals will require considerable 
electronic communication of data and other information among the MPSA 
Consortium components and between the components and the NIH. Consortium 
members will be required to transfer data accurately and effectively.

Biomarker Units

Biomarker units will generate and validate biomarkers relevant to the 
progression of BPH, response to therapy, and the concurrent development of 
prostate cancer. The biomarkers will be generated using local samples, then 
tested on the MTOPS serum and prostate sample set.

Pathology Coordinating Center

The Pathology Coordination Center will read the prostate biopsies, and 
maintain and distribute the MTOPS serum and prostate samples to members of 
the consortium. Under the direction and guidance of the Steering Committee, 
the Pathology Coordinating Center may generate specialized sample sets and 
reagents, and scale-up assays to allow testing in large number of samples. 
These research resources will be made available to the Biomarker Units and, 
after discussion by the Steering Committee, to the wider research community. 

The Pathology Coordination Center will also provide travel and meeting 
support for the Steering Committee and other committees of the MPSA 
Consortium.

Data Coordinating Center

The MTOPS Data Coordinating Center, supported separately from the MPSA 
Consortium, will maintain the database that contains clinical and laboratory 
data on patients enrolled in the MTOPS study. The MTOPS Data Coordinating 
Center will also perform a follow-up study of the MTOPS participants by 
questionnaire and/or death certificates. The MTOPS Data Coordinating Center 
will establish and maintain the Internet-based mechanism for rapid data and 
document transmission and electronic communication among participants in the 
MPSA Consortium and between the MPSA Consortium and the NIH. These databases 
and websites will serve the needs of all Units established by this initiative 
and will be an important interface between the MPSA Consortium and the larger 
research community.

2. NIH Staff Responsibilities

The NIDDK and NIA will each identify one Program Officer and one Project 
Scientist.

NIH Program Officers will provide normal stewardship and administrative 
oversight. They will review the scientific progress of the individual 
components and review the components for compliance with operating policies 
developed by the Steering Committee. NIH Program Officers may withhold 
support, suspend, or terminate an award for lack of scientific progress or 
failure to adhere to policies established by the Steering Committee.  The NIH 
Program Officers reserve the right to approve moving from one phase of a 
project to the next.

NIH Project Scientists will have substantial scientific-programmatic 
involvement during conduct of this activity, through technical assistance, 
advice, and coordination above and beyond normal program stewardship for 
grants, as described below. The dominant role and prime responsibility for 
the project as a whole resides with the awardees, although specific tasks and 
activities in carrying out the studies will be shared by awardees and the 
NIH.

o NIH Project Scientists will coordinate and facilitate the MPSA Consortium 
programs and be members of the Steering Committee and its subcommittees. 
Other NIH Staff with relevant expertise may participate in the Steering 
Committee and subcommittees as non-voting members.

o NIH Project Scientists will help the Steering Committee develop and draft 
operating policies and policies addressing recurring situations that require 
coordinated action.
 
o The NIH Project Scientists may contribute, through review, comment, 
analysis, and/or co-authorship, to reporting results of the studies conducted 
by the MPSA Consortium to the research community and interested lay 
organizations. Co-authorship by the NIH Project Scientists will be subject to 
approval in accordance with NIH policies regarding staff authorship of 
publications resulting from extramural awards. 

o NIH will form an MPSA Advisory Panel that comprises outside advisors (non 
grantees) picked by NIH program staff. The MPSA Advisory Panel will meet 
regularly to review the progress of the MPSA Consortium and to advise the NIH 
of scientific developments and opportunities that may enhance the achievement 
of the MPSA Consortium goals.

o If necessary to preserve the samples and data about them and/or to continue 
the research, the NIH reserves the right to require the transfer to an 
eligible third party any appropriate serum and prostate samples, related 
reagents, and pertinent data generated as the result of participation in 
research supported under these awards. Third parties supported under these 
awards must be informed of this right.

3. Collaborative Responsibilities

Steering Committee

o The Steering Committee will be the main governing board of the MPSA 
Consortium. It will develop collaborative protocols and quality control 
standards, set priorities for biomarker validation using the MTOPS serum and 
prostate samples, approve the design and implementation of all collaborative 
studies, facilitate the conduct and monitoring of all collaborative studies, 
analyze and interpret collaborative study data, and report collaborative 
study results. Studies will proceed to the validation stage only with the 
concurrence of the Steering Committee. It will also identify technological 
impediments to success and strategies to overcome them, develop shared 
software tools for disseminating information about the MPSA Consortium, 
identify opportunities for sharing techniques and tools with a wider research 
community, and decide when biomarkers should be made available to the 
research community.

o The Steering Committee will be composed two investigators from each 
Biomarker Unit, the Pathology Coordination Center, the MTOPS Data 
Coordinating Unit, and the two NIH Project Scientists. The two investigators 
from each component will share one vote. The NIH Project Scientists will 
share one vote. The Steering Committee will select a chair who will be 
someone other than an NIH Program Officer.

o The NIH reserves the right to augment the scientific expertise of the 
Steering Committee when necessary.

o There will be two Steering Committee meetings annually, both in the 
Washington, DC, area, at times agreed upon by the Steering Committee and the 
NIH. The first meeting of the MPSA Consortium will be a Planning Meeting in 
the Washington, DC, area soon after grants are awarded. At the Planning 
Meeting, the Steering Committee will be formed and will select a chairperson 
from among the members who represent the awardees. At the Planning Meeting, 
the Steering Committee may: (a) draft a charter to detail policies and 
procedures, a process for monitoring compliance with the policies and 
procedures, and a process for recommending that the NIH Program Officer(s) 
act on evidence of non-compliance of any Consortium component with Steering 
Committee policies, (b) agree upon the terms of the charter, (c) discuss the 
approaches for generating and validating biomarkers that were proposed in the 
project applications and any relevant new information, and set initial 
priorities for the projects that will be pursued and for new technologies 
(tissue arrays) to be developed, (d) discuss and set initial genotypic and 
phenotypic parameters required to characterize the patients, (e) discuss and 
set initial standards for validating the biomarkers for further biological 
studies and such uses as testing prevention or early detection strategies, or 
therapies, or diagnostic imaging technologies, (f) develop a bioinformatics 
subcommittee whose membership will include the key research scientists 
responsible for bioinformatics, NIH Project Scientist(s) or program staff 
with relevant expertise, and outside advisors as needed. An Internet-based 
electronic communications mechanism will be discussed and will be implemented 
by the MTOPS Data Coordinating Unit.

o At their first meeting each year, the Steering Committee will formulate 
plans for any workshops or symposia to be held.

o At the second and subsequent meetings, the Steering Committee will refine 
the MPSA Consortium"s scientific objectives and implementation as necessary, 
consistent with the progress  of the individual components and the MPSA 
Consortium.

o At any time during the MPSA Consortium, the Steering Committee may examine 
the characterization and validation data for biomarkers derived by the MPSA 
Consortium components and decide when a test is sufficiently validated that 
it may be distributed to the research community for further investigations or 
applications.

o The Steering Committee will plan workshops to which non-MPSA Consortium 
participants will also be invited to (a) enable the MPSA Consortium to 
explore scientific or technologic innovation that occurs during the course of 
the project, (b) inform the research community of the progress made toward 
derivation or validation of biomarkers, and (c) inform the research community 
of any technological advances related to derivation and validation of 
biomarkers. The NIH Project Scientist(s), the MPSA Advisory Panel, and other 
NIH staff will provide the Steering Committee with advice on participants for 
the workshops and symposia.

o The Steering Committee may establish subcommittees, as it deems 
appropriate, NIH Project Scientist(s) and other NIH staff will serve on 
subcommittees as they deem appropriate.

4. Arbitration

Any disagreement that may arise on scientific/programmatic matters (within 
the scope of the U01 award) between awardees and the NIH may be brought to 
arbitration. An arbitration panel will be composed of three members: one 
member selected by the Steering Committee (with the NIH Project Scientist(s) 
not voting) or by the individual awardee in the event of an individual 
disagreement, a second member selected by the NIH Project Scientist(s), and 
the third member selected by the two previously selected members. This 
special arbitration procedure in no way affects the awardee"s right to appeal 
an adverse action that is otherwise subject to appeal in accordance with the 
PHS regulations at 42 CFR Part 50, Subpart D and HHS regulation at 45 CFR 
Part 16.

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS

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

The inclusion of women and children does not apply.

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

REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS

NIH policy requires education on the protection of human subject participants 
for all investigators submitting NIH proposals for research involving human 
subjects.  This policy announcement is found in the NIH Guide for Grants and 
Contracts Announcement dated June 5, 2000, at the following website: 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

URLS IN NIH GRANT APPLICATIONS OR APPENDICES

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

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.

LETTER OF INTENT

Prospective applicants are asked to submit a letter of intent by February 20, 
2002. The letter should include 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 IC staff to estimate the potential review workload 
and plan the review.

The letter of intent is to be sent to:

Chief, Review Branch 
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Boulevard, Rm. 752 MSC 5452
Bethesda, MD  20892-5452
(for express/courier service: Bethesda, MD  20817)
Telephone:  (301) 594-8897
FAX:  (301) 480-3505
E-mail:  fc15y@nih.gov

APPLICATION PROCEDURES

The PHS 398 research grant application instructions and forms (rev. 5/2001) 
at http://grants.nih.gov/grants/funding/phs398/phs398.html must be used in 
applying for these grants. This version of the PHS 398 is available in an 
interactive, searchable format.  For further assistance contact GrantsInfo, 
Telephone 301/435-0714, Email:  GrantsInfo@nih.gov.

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 (DK-02-027) on the label. Failure to use this label could result in 
delayed processing of the application such that it may not reach the review 
committee in time for review.  In addition, the RFA title and number must be 
typed on line 2 of the face page of the application form and the YES box must 
be marked. The RFA label is also available at: 
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf.

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

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

At the time of submission, two additional copies of the application must be 
sent to:

Dr. Francisco O. Calvo
Chief, Review Branch 
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Boulevard, Rm. 752 MSC 5452
Bethesda, MD  20892-5452
(for express/courier service: Bethesda, MD  20817)
Telephone:  (301) 594-8897
E-mail:  fc15y@nih.gov

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.

Applicants may apply for a Biomarker Unit, a Pathology Coordination Center, 
or both. If an applicant applies for both, separate applications must be 
submitted

1. General Application Format Instructions

Applicants are encouraged to submit and describe their own ideas about how 
best to meet the goals of the cooperative study and their specific protocols, 
and they are expected to address issues identified under "TERMS AND 
CONDITIONS OF AWARD FOR THE MPSA CONSORTIUM" and "SPECIAL REQUIREMENTS" 
sections of the RFA. 

2. Applications for Biomarker Units

It is expected that either the Principal Investigator or co-investigator(s) 
will have demonstrated and published experience in basic research studies 
that focus predominantly on BPH utilizing human tissue samples. In addition, 
either the Principal Investigator or co-investigator(s) must have 
demonstrated expertise in multi-center clinical trials focused on BPH 
treatment. One of the investigators must demonstrate expertise in 
translational research studies focused on prostate diseases.    

Applicants should discuss their rationale for the design and derivation of 
new biomarkers or for altering and improving existing biomarkers based on 
their experience with biomarkers and their knowledge of basic, translational, 
and clinical prostate research. Applicants should describe the extent to 
which they plan to characterize any biomarkers they derive or refine, the 
methods that they will use to characterize the biomarkers, the rationale for 
choices of methods, and how generally applicable the methods are, or will be, 
for benign and malignant prostate diseases. Applicants are expected to 
discuss assay optimization, quality control, and assay performance. 
Applicants are expected to discuss methods for establishing priorities among 
biomarkers, identify the standards they will apply to validate a proposed 
biomarker, the rationale for the choices, how generally applicable the 
validation standards are, or will be, for benign and malignant prostate 
disease, and the purpose(s) for which they anticipate their biomarkers might 
be used. The roles and expertise of all key personnel, collaborators, and 
consultants who are associated with this part of the application should be 
thoroughly documented. 

Applicants should define the technologic approaches they will use, or any 
technology that they propose to develop to achieve the goals of biomarker 
generation, refinement, characterization, and validation. The roles and 
expertise of all key personnel, collaborators, and consultants who are 
associated with this part of the application should be thoroughly documented.

2. Applications for the Pathology Coordination Center

Applicants for the Pathology Coordination Center must have published and 
documented their experience in reading human prostate biopsy samples and 
basic and clinical research studies related to human BPH tissue. Applicants 
should discuss methods to store, handle, and retrieve MTOPS serum and 
prostrate biopsy samples, including both paraffin and OTC-embedded samples.  
Applicants may also propose to develop specialized serum or prostate protein 
arrays, layered expression arrays, or tissue arrays that allow rapid testing 
of biomarkers. Applicants should also indicate their familiarity and 
capability for performing multiple assays (generally ELISAs or bead-based 
multi-analyte systems) either sequentially or in parallel on these samples. 
For example, it would be more efficient to test 10-100 tests at once on a 
single 0.5 ml sample, than to do a similar number of tests individually. 
These tests will be funded by the individual Biomarker Units, but might be 
performed at the Pathology Coordination Center.

Applicants should discuss the administrative structure of the coordinating 
unit and plans for providing administrative support for up to five meetings a 
year. 

3. Interactions / Data sharing (applies to Biomarker and Pathology 
Coordination Centers)

The application should include the description of an internal advisory board 
consisting of the Principal and co-investigators and other important 
personnel should oversee the daily operation of the unit. Applicants should 
describe how the unit will fit into, augment, and be supported by the parent 
institution and plan for designating an alternate or replacement Principal 
Investigator should it become necessary.

Applicants should describe the Internet-based mechanism for rapid electronic 
communication among participants and the NIH, the structure of their 
databases and websites for communication within the MPSA consortium and with 
the research community. Applicants should describe issues of data validity, 
security, and confidentiality.

Applicants should discuss how they would interact with other MPSA Consortium 
components and the general research community. In this part of the "Research 
Plan," applicants must include specific plans for responding to the "Terms 
and Conditions of Award" section. Applicants should state their willingness 
to collaborate and share data freely with the other MPSA Consortium 
components and the wider research community. Applicants must include a data 
sharing plan and copies of all Material Transfer Agreements used by all 
institutions involved in the application. Applicants are encouraged to use 
the NIH Simple Letter of Agreement to transfer materials, available at 
http://www.nih.gov/od/ott/RTguide_final.htm#guide.  Applicants should discuss 
their willingness to serve on the Steering Committee and other Consortium 
committees and should state their willingness to follow the common protocols 
that will be developed by the Steering Committee, particularly those that 
relate to setting priorities for biomarker validation and the standards for 
characterization and validation. Applicants must state their willingness to 
plan and attend workshops and symposia.

Applicants should describe how their unique blend of experience could 
contribute to the collective efforts of the MPSA Consortium. Applicants 
should also describe how they will comply with the involvement of NIH Project 
Scientist(s) and fulfill the responsibilities of Consortium components to 
work together cooperatively. Applicants should describe their experience 
with, and capability for, Internet-based communication and ideas for 
facilitating electronic communication and other interactions among the MPSA 
Consortium components, NIH, and the general research community.

The scientific review group will evaluate the adequacy of the proposed plan 
for sharing and data access. Comments on the plan and any concerns will be 
presented in an administrative note in the summary statement. The adequacy of 
the plan will be considered by NIH program staff and will be important in 
determining whether the grant shall be awarded. The sharing plan(s) as 
approved, after negotiation with the applicant when necessary, will be a 
condition of the award. Evaluation of non-competing continuation applications 
will include assessment of the effectiveness of research resource release.

Applicants are reminded that the grantee institution is required to disclose 
each subject invention to NIH within two months after the inventor discloses 
it in writing to grantee institutional personnel responsible for patent 
matters. The awarding Institute reserves the right to monitor awardee 
activity in this area to ascertain if patents or patent applications on 
biomarkers or other patentable subject matter are adversely affecting the 
goals of this RFA.

4. Budget Instructions

Common to Biomarker Units and Pathology Coordinating Center

o Applicants who have additional funds to support ("leverage") the 
application should indicate the source of funds (institutional, R01, P01, 
P30, etc.) that permit them to accomplish the project goals. Subcontract 
budgets should be a separate page, and the subcontract indirect costs should 
be calculated and listed in the usual place as part of the direct costs of 
the budget. 

o Applicants must budget for travel and per diem expenses for participation 
in the MPSA Consortium Steering Committee, subcommittees, workshops, and 
symposia. Applicants should budget for three trips to the Bethesda, MD, area 
each year.

Biomarker units only

o Only direct costs associated with each subcontract will count toward the 
direct costs cap of $300,000 on the budget for the each year.

o Funds should be requested for testing and validating new biomarkers on the 
MTOPS samples at the Pathology Coordinating Center and at other Biomarker 
Units. Applicants are instructed to make budget requests for funds to travel 
to Steering Committee meetings

Pathology Coordination Center only

o Applicants should include funds to move the samples, if necessary, to their 
own site. 

o Applicants should include travel support for 15 additional outside 
consultants to attend Steering and other committee meetings and workshops in 
the Bethesda, MD, area each year.

REVIEW CONSIDERATIONS

All applications will be judged on the basis of the scientific merit of the 
proposed project and the documented ability of the investigators to meet the 
RESEARCH OBJECTIVES of the RFA. Although the technical merit of the proposed 
protocol is important, it will not be the sole criterion for evaluation of a 
study. Other factors considered to be important for review include 
demonstrated expertise in clinical prostate disease as applied to the 
derivation and validation of biomarkers of human disease, a multi-
disciplinary team of collaborators, substantial interactions among 
collaborating researchers, demonstration of appropriate facilities and 
resources, willingness to share data and reagents freely.

Review Method

Upon receipt, applications will be reviewed for completeness by the CSR and 
responsiveness by the NIH. Incomplete applications will be returned to the 
applicant without further consideration. 

Applications that are complete and responsive to the RFA will be evaluated 
for scientific and technical merit by an appropriate peer review group 
convened by the NIH in accordance with the review criteria stated below. As 
part of the initial merit review, all applications will receive a written 
critique and undergo a process in which only those applications deemed to 
have the highest scientific merit, generally the top half of the applications 
under review, will be discussed, assigned a priority score, and receive a 
second level review by the appropriate National Advisory Council.             

Review Criteria

The peer review group will assess the scientific merit of the applications 
and related factors using the following criteria:

1. Innovation. Does the project employ novel concepts, approaches, or method? 
Is the project original and innovative? Does the project challenge existing 
paradigms or develop new methodologies or technologies? Will the approaches 
advance the field of prostate biomarkers or prostate pathophysiology?

2. Approach. Are the conceptual framework, design, methods, and analyses 
adequately developed and appropriate to the aims of the project? Does the 
applicant acknowledge potential problem areas and consider alternative 
tactics? Are the parameters chosen to characterize and validate the 
biomarker(s) sufficient and appropriate? Are the standards chosen to validate 
the biomarker(s) for testing early detection, prevention, therapy, or imaging 
appropriate and adequate? Will the assay(s) be sufficiently optimized to use 
in a multi-analyte assay? Can these approaches be used to derive biomarkers 
in addition to those proposed?

3. Investigators. Are the principal investigator and his/her collaborators 
appropriately trained and well suited to carry out this work? Do they have 
the necessary clinical and research knowledge and experience with human BPH 
tissue biopsies? To what extent do these investigators have the necessary 
complementary skills? Do the investigators have skills in both prostate 
disease and biomarkers? Have collaborations been established or consultants 
identified to provide the appropriate depth and breadth of scientific 
expertise required for the project? Will this team of investigators 
contribute unique skills to the overall Consortium? Do the investigators have 
demonstrated experience in working in multi-center studies? Will the 
investigators work effectively with other members of the Consortium?

4. Environment. Are the facilities for biomarker and generation and 
validation appropriate to support the endeavor? 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 and incorporate the best use of collaborative 
arrangements? Is there evidence of institutional support?

5. Significance. Do the biomarker(s) proposed for derivation/ 
characterization/validation address an important need for the prostate 
research community? What is the immediacy of the research opportunity? Over 
the project period, is there potential for the group to develop biomarkers 
other than those specified in the application?

Pathology Coordination Center 

1. Do the investigators have demonstrated research and clinical expertise in 
reading human BPH biopsies? Have they published research studies involving 
human BPH tissue? Are there adequate plans for storing, handling, and 
distributing serum and prostate samples? Does the Center employ novel 
concepts, approaches, or methods? Are the principal investigator and 
collaborators appropriately trained and well suited to provide support for 
multiple investigative teams? Do the investigators have demonstrated 
experience in working in multi-center studies? Are they willing to cooperate 
with other investigators in the consortium? Can the site perform the 
biomarker assays either one at a time or in a multi-analyte assay? Are there 
adequate plans for providing meeting support for the MPSA Consortium?

Additional Considerations for Biomarker Units and Pathology 
Coordinating Center

1. Interactions. Are there adequate plans for effective interaction and 
coordination among Consortium components and the NIH? Are the proposed plans 
to share assays, tools, data, and tests adequate? Do the investigators state 
their willingness to collaborate extensively and share information fully? Are 
the Material Transfer Agreements straightforward? Do the investigators state 
their willingness to abide by the priorities and policies agreed upon by the 
Steering Committee? Have the applicants proposed sound strategies for 
communication among themselves, with the other MPSA components, and with 
the NIH?

2. Budget. Assess the appropriateness of the proposed budget and duration in 
relation to the proposed research. Does the budget for fundamental 
infrastructure, biomarker development, characterization and validation, and 
technology development indicate that the applicants understand the 
requirements of managing this sort of enterprise? 

3. The scientific review group will evaluate the adequacy of the proposed 
plan for sharing and data access, with comments on the following elements: 
have the applicants addressed data sharing policies, confidentiality issues, 
and security considerations? Are there adequate plans for open access to 
these databases and websites by the general research community?  Comments on 
the plan and any concerns will be presented in an administrative note in the 
summary statement. The adequacy of the plan will be considered by NIH program 
staff and will be important in determining whether the grant shall be 
awarded. The sharing plan(s) as approved, after negotiation with the 
applicant when necessary, will be a condition of the award. Evaluation of 
non-competing continuation applications will include assessment of the 
effectiveness of research resource release.

4. 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.

AWARD CRITERIA

The intent of this RFA is to enable the NIH to assemble a Consortium of 
highly qualified investigators whose complementary scientific skills and 
expertise will enable them to achieve the goal of deriving and validated 
biomarkers for prostate disease. The NIH will choose Biomarker Units and a 
Pathology Coordinating Center for the Consortium that will collectively 
provide the most creative approaches to biomarker design and validation, and 
have a range of research focus, experience, technology, and resources to 
ensure that a range of biomarkers are rapidly derived and validated.

Applications recommended by the NIH Advisory Councils will be considered for 
award based upon (a) scientific and technical merit as determined by peer 
review, (b) the importance of the proposed biomarkers for detection, 
prevention, and therapy of prostate diseases, (c) the degree of originality, 
innovation, and diversity of Biomarker, (d) the creativity of the approaches 
and technologies, (e) the likelihood for substantial contribution by the 
applicants to a successful collaborative effort, (f) the evidence for 
willingness to work cooperatively, (g) the quality and availability of the 
basic science infrastructure and resources, (h) program balance, including 
sufficient compatibility of features to make a successful collaborative 
program a reasonable likelihood, and (i) the availability of funds.

Schedule

Public Information Meeting:       January 2002
Letter of Intent Receipt Date:    February 20, 2002
Application Receipt Date:         March 20, 2002
Peer Review Date:                 June-August 2002
Council Review:                   September 2002
Earliest Anticipated Start Date:  September 30, 2002

INQUIRIES

A public information meeting will be held by Phone Conference in January 
2002. The date and time of this meeting, answers to frequently asked 
questions, and other updates about this RFA will be posted on the NIDDK 
website http://www.niddk.nih.gov/fund/crfo/highlights.htm as they are 
developed. Applicants are highly encouraged to visit this website regularly 
in the course of preparing applications. Potential applicants are encouraged 
to subscribe to the MPSA Consortium Discussion List at 
http://list.nih.gov/archives/mpsa_consortium-l.html. These sites will 
contain the most current information available.

Written and telephone inquiries concerning this RFA are encouraged. The 
opportunity to clarify any issues or questions from potential applicants is 
welcome. Direct inquiries regarding programmatic issues that are not 
addressed at the website to:

Robert A. Star, M.D.
Division of Kidney, Urologic, and Hematologic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Boulevard, Room 647 MSC 5456
Bethesda, MD  20892-5456
Tel:  (301) 594-7717
Fax:  (301) 496-3510
E-mail:  rs301p@nih.gov

Frank Bellino, Ph.D.
Biology of Aging Program
National Institute on Aging
7201 Wisconsin Avenue, Suite 2C231 MSC 9205
Bethesda, MD  20892-9205
Telephone:  (301) 496-6402
FAX:  (301) 402-0010
Email:  fb12a@nih.gov

Direct inquiries regarding fiscal matters to:

Teresa Farris Marquette
Division of Extramural Activities 
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Boulevard, Room 728 MSC 5456
Bethesda, MD  20892-5456
Tel:  (301) 594-7682
Fax:  (301) 480-3504
E-mail:  tf102y@nih.gov

Linda Whipp
Grants and Contracts Management Office
National Institute on Aging
7201 Wisconsin Avenue, Suite 2N212, MSC 9205
Bethesda, MD  20892-9205
Telephone:  (301) 496-1472
FAX:  (301) 402-3672
Email:  lw17m@nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No. 
93.849 and 93.866. Awards are made under authorization of the Public Health 
Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 
99-158, 42 USC 241 and 285) and administered under NIH grants policies and 
Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. This program is not 
subject to the intergovernmental review requirements of Executive Order 12372 
or Health Systems Agency review.

The PHS strongly encourages all grant 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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