SBIR/STTR: CIRCULATING CELLS AND DNA IN CANCER DETECTION

RELEASE DATE:   June 9, 2004

RFA NUMBER:  RFA-CA-06-001 - This RFA has been replaced by 
RFA-CA-07-027(SBIR [R43/R44]) and 
RFA-CA-07-028(STTR [R41/R42]) 

EXPIRATION DATE:  October 13, 2005

Department of Health and Human Services (DHHS)

PARTICIPATING ORGANIZATION:  
National Institutes of Health (NIH) 
 (http://www.nih.gov/)

COMPONENT OF PARTICIPATING ORGANIZATION:
National Cancer Institute (NCI)  
 (http://www.nci.nih.gov/)

CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S): 93.393, 93.394

LETTER OF INTENT RECEIPT DATE: January 17, 2005; May 16, 2005; September 14, 
2005

APPLICATION RECEIPT DATE: February 14, 2005; June 13, 2005; October 12, 2005

THIS RFA CONTAINS THE FOLLOWING INFORMATION

o Purpose of this RFA
o Research Objectives
o Mechanisms of Support 
o Project Period and Amount of Award
o Funds Available
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Where to Send Inquiries
o Letter of Intent
o Submitting an Application
o Supplementary Instructions 
o Peer Review Process
o Review Criteria
o Receipt and Review Schedule
o Award Criteria
o Required Federal Citations

NOTICE: This Request for Application (RFA) must be read in conjunction with 
the current OMNIBUS SOLICITATION OF THE NATIONAL INSTITUTES OF HEALTH, 
CENTERS FOR DISEASE CONTROL AND PREVENTION, and FOOD AND DRUG ADMINISTRATION 
FOR SMALL BUSINESS INNOVATION RESEARCH (SBIR) SMALL BUSINESS TECHNOLOGY 
TRANSFER (STTR) GRANT APPLICATIONS.  The solicitation (see 
http://grants.nih.gov/grants/funding/sbirsttr1/index.pdf [PDF] or 
http://grants.nih.gov/grants/funding/sbirsttr1/index.doc [MS Word]) contains 
information about the SBIR and STTR programs, regulations governing the 
programs, and instructional information for submission. All of the 
instructions within the SBIR/STTR Omnibus Solicitation apply with the 
exception of the following.

o Special receipt dates; and    
o Initial review convened by the NCI Division of Extramural Activities.    

PURPOSE OF THIS RFA 

The Division of Cancer Prevention of the National Cancer Institute invites 
small business applications for research projects to develop novel 
technologies for capturing, enriching, and preserving exfoliated abnormal 
cells and circulating DNA from body fluids or effusions and to develop 
methods to concentrate these cells and DNA for cancer biomarker detection. 

In body fluids, such as sputum, the number of exfoliated tumor cells is often 
low compared to the number of normal cells, making it difficult to detect 
these abnormal cells by routine cytopathology.  Separation of dysplastic 
cells from degenerating cells and cells undergoing non-specific reactive 
changes is problematic. Moreover, exfoliated cells are frequently 
contaminated with normal cells, bacteria, and cellular debris. Therefore, 
enrichment methods are needed to allow for routine detection and molecular 
analysis of small numbers of exfoliated cells.

Circulating extracellular DNA was first reported in 1948. It has been shown 
that the circulating DNA in the blood of cancer patients has genetic 
characteristics identical to those of the primary tumors. Thus, circulating 
DNA is an important material that may be useful for cancer detection. 
Currently available methods for isolating undegraded circulating DNA are 
limited, and there is a need to develop novel methods which improve the yield 
of undegraded DNA and to adapt detection assays so that this DNA can be used 
to detect mutations, microsatellite instabilities, loss of heterozygosity, 
epigenetic changes, and other molecular genetic changes. 

This RFA will utilize the Small Business Innovation Research (SBIR) and Small 
Business Technology Transfer (STTR) mechanisms, but will be run in parallel 
with a program announcement of identical scientific scope (PA-04-035) that 
will utilize the exploratory/developmental (R21) grant mechanism.

RESEARCH OBJECTIVES

Background

Cellular and molecular changes that ensue during tumor progression occur over 
a number of years and in an apparently stochastic manner.  For example, it 
takes an average of 15 to 20 years for a small adenomatous polyp to become 
malignant.  Prior to the appearance of a morphologically identified 
precancerous lesion, numerous genetic and molecular alterations have 
occurred.  During the early stages of cancer development, there is a window 
of opportunity to detect precancerous cells with genetic or molecular 
biomarkers that identify and characterize their progression towards cancer.  
Finding molecular and genetic biomarkers of malignancy is an extraordinary 
opportunity for the NCI and is particularly important in detecting the 
emergence of precancerous cell populations. In these earliest stages of 
neoplasia, lesions are more likely to be amenable to eradication.  This 
principle has been well-demonstrated in cervical neoplasia, where screening 
for dysplastic exfoliated cells can result in a 70 percent or greater 
reduction in mortality due to cervical cancer.  Detection of genetic 
abnormalities in preneoplastic lesions poses challenges because of the small 
size of lesions, the heterogeneity of precancerous cells, and the relatively 
low number of abnormal cells compared to normal cells.  
   
Rationale
   
More than 80 percent of human tumors (e.g. colon, lung, prostate, oral 
cavity, esophagus, stomach, uterine cervix, and bladder) originate from 
epithelial cells, often at a mucosal surface, and are clonal in origin.  
Cells from these tumors exfoliate spontaneously into blood, sputum, urine, 
and various effusions.  Abnormalities within these exfoliated cells could be 
used to detect and identify precancerous lesions or very early stage cancers 
if highly sensitive technologies were available to identify the presence of a 
few abnormal cells among millions of normal cells.  For example, PCR has been 
used to detect mutant DNAs in neoplastic exfoliated cells; mutations have 
been detected in ras genes present in stool samples obtained from patients 
with colorectal cancer, and in p53 from the urine of patients with bladder 
cancer and in the sputa of patients with lung cancer.  Assays to detect 
genetic mutations, microsatellite instability, or hypermethylation may be 
adapted for use with exfoliated cells.  As these assays are complex and 
technically challenging, their general use will require the development of 
novel technologies for isolating and enriching abnormal exfoliated cells.
   
Studies performed in the early 1970s showed that increased quantities of DNA 
are found in the plasma of patients suffering from different malignancies, 
but it was not until the 1990s that this circulating DNA was shown to exhibit 
tumor-related alterations.  Mutant DNA has been found in the plasma of 
patients with colorectal, pancreatic, biliary tree, skin, head-and-neck, 
lung, breast, kidney, ovarian, nasopharyngeal, liver, bladder, gastric, 
prostate, and cervical cancers as well as in haematologic malignancies.  
Allelic imbalance (AI), which involves the loss or gain of chromosomal 
regions, is found in many cancers.  AI can be detected in genomic tumor DNA 
released into the blood after cellular necrosis or apoptosis.  These 
observations indicate that plasma/serum may be a suitable specimen source for 
noninvasive diagnostic, prognostic, and follow-up tests for cancer
   
Barriers

Precancerous exfoliated cells can be identified by cytologic examination of 
washings or brushings from bronchi, oral cavity, esophagus, stomach, bile and 
pancreatic ducts, as well as of sputum and urine specimens. However, the 
detection of these exfoliated cancer cells by routine cytopathological 
examination is very difficult because the number of abnormal cells in the 
specimens is usually very low compared to the number of normal cells.  It is 
also difficult to distinguish low grade dysplasia from non-specific reactive 
or inflammatory changes due to the low sensitivity and specificity of current 
diagnostic methodologies.  This is particularly true of urine cytology, where 
most low-grade papillary lesions are missed by cytologic examination.  Even 
with new PCR-based technologies with enhanced sensitivity, current 
technologies for isolating exfoliated cells are too inefficient to be of 
practical utility.   Therefore, the development of novel, high-throughput, 
sensitive technologies for sample preparations is a prerequisite for the 
successful detection of the small number of exfoliated cells or of the small 
amounts of DNA, RNA and proteins in these cells. 
   
There are a variety of approaches to detect and analyze precancerous and 
cancerous cells in body fluids (e.g., cytopathological analysis, morphometric 
analysis, molecular biomarkers for specific receptors or genetic changes, 
Fluorescence in Situ Hybridization [FISH] analysis, or PCR-based analysis).  
The selection of approach, in many instances, depends on the type of 
biological specimens (sputum, bronchial washing, cervical brushing, voided 
urine, etc.).  Given that the concentration of the atypical epithelial cells 
can be very low compared to that of normal cells, all of these approaches 
require between 1 to 10,000 and 1 to million enrichments of the atypical 
cells.  Currently, there are two broad categories of enrichment methods: 
mechanical (centrifugation, cytospin, sucrose gradients, etc.) and antibody-
based selection with mechanical separation (FACS – flow-assisted cell 
sorting, MACS - magnetic assisted cell sorting, etc.).  While these two types 
of enrichment processes can be used in series to improve the yield, none of 
the currently available methods achieve sufficient enrichment of atypical 
cells to allow them to be routinely used for cancer detection. 
   
The single largest barrier to using circulating DNA for cancer detection is 
the amount of circulating undegraded DNA that can be isolated is low, making 
it unsuitable for currently available assay technologies.  Several factors 
affect the yield and purity of circulating DNA.  Intracellular nuclease 
activity in both apoptotic and necrotic cells in a particular organ affect 
the degree of DNA degradation found in body fluids. Also, the degree to which 
a particular tissue is represented in the total circulating DNA is dependent 
on the mechanism and efficiency by which apoptotic cells are eliminated from 
the tissue.
   
As with any other diagnostic technique, practical application of circulating 
DNA technology is dependent on concurrent increase in the sensitivity and 
reproducibility of molecular based-assays.  The potential use of circulating 
DNA for cancer detection could be greatly enhanced by developing isolation 
methods that result in less degradation and by adapting assay methods to use 
the low amounts that can be isolated.  Because of the limitations of 
“conventional” markers, there has been a search for additional sources of 
specificity so as to expand the target pool of cancer-associated molecules.  
Circulating cells and DNA offer such opportunity for detection molecular 
aberrations in plasma/serum, or other body fluids, that accurately reflect 
the situation in primary tumor.  This will, however, require the development 
of methodological consistencies so as to allow valid comparisons between 
various assays based on circulating cells or DNA.

Objective and Scope
   
The primary purpose of this initiative is to encourage the development of 
technologies for isolating and characterizing exfoliated cells, circulating 
cells, and plasma/serum DNA. A secondary purpose is the analytical validation 
of existing and/or newly developed technologies for their usefulness in 
cancer detection. Analytical validation refers to the measurement of 
sensitivity and reproducibility of the proposed assay/technology.  The long-
term goal of the technology development is to identify a panel of well-
characterized biomarkers derived from exfoliated cells and/or circulating DNA 
that can be sampled in a clinical setting.  These methodologies will be 
tested and validated in future population-based clinical trials, and 
integrated into a comprehensive information system that will be developed 
under the Early Detection Research Network (www.cancer.gov/edrn). In pursuit 
of these goals, the NCI invites applications which address the following 
areas: 
   
o Development of high-throughput, high-yield technologies for isolating 
exfoliated cells, circulating cells and DNA in body fluids; 

o Development of methods for enrichment and preservation of exfoliated cells, 
circulating cells and DNA isolated from body fluids; 

o Development of sensitive, high-throughput molecular, cytomorphometric, 
immunologic, and other relevant technologies to isolate and characterize 
tumor cells in malignant effusions for detection of low tumor burden, to help 
distinguish reactive cells from tumor cells, and to perform accurate assays 
on circulating DNA;

o Validation of the sensitivity and reproducibility of current technologies 
for isolating and characterizing exfoliated cells, circulating cells and DNA 
isolated from body fluids.

MECHANISMS OF SUPPORT

This RFA uses the SBIR and STTR mechanisms, which are set-aside programs. As 
an applicant, you will be solely responsible for planning, directing, and 
executing the proposed project. Future unsolicited, competing-continuation 
applications based on this project will compete with all SBIR/STTR 
applications and will be reviewed according to the customary peer review 
procedures. The anticipated award date is approximately 9-11 months from the 
respective receipt date.  Applications that are not funded in the competition 
described in this RFA may be resubmitted as NEW SBIR/STTR applications using 
the standard receipt dates for NEW applications described in the current 
SBIR/STTR Omnibus Solicitation. As there are multiple receipt dates, it is 
possible that an unfunded application can be resubmitted under this RFA as a 
revised application.

This RFA uses just-in-time concepts. It also uses the modular budgeting as 
well as the non-modular budgeting formats. Specifically, if you are 
submitting an application budget of $100,000 total costs (direct, F&A and 
fee) or less, use the modular budget format.  For applications requesting 
more than $100,000, use the non-modular budget format.  Instructions for both 
are described in the current SBIR/STTR Omnibus Solicitation.  This program 
does not require cost sharing as defined in the current NIH Grants Policy 
Statement at 
http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part2.htm. 

Except as otherwise stated in this RFA, awards will be administered under NIH 
grants policy as stated in the NIH Grants Policy Statement, December 2003, 
available at  http://grants.nih.gov/grants/policy/nihgps_2003/.  

Applications may be submitted for support as Phase I STTR (R41) or Phase I 
SBIR (R43) grants; Phase II STTR (R42) or Phase II SBIR (R44) grants; or the 
SBIR/STTR FAST-TRACK option as described in the SBIR/STTR Omnibus 
Solicitation.  Phase II applications in response to this RFA will only be 
accepted as competing continuations of previously funded NIH Phase I 
SBIR/STTR awards.  A Phase II application must be a logical extension of the 
Phase I research but not necessarily a Phase I project supported in response 
to this RFA.  Fast Track applications will benefit from expedited evaluation 
of progress following the Phase I feasibility study for transition to Phase 
II funding for expanded developmental work.   

PROJECT PERIOD AND AMOUNT OF AWARD

The SBIR/STTR Omnibus Solicitation indicates the statutory guidelines of 
funding support and project duration periods for SBIR and STTR Phase I and 
Phase II awards.  For this RFA budgets up to $100,000 in total costs and time 
periods up to 1 year for Phase I can be requested.  Budgets up to $500,000 in 
total costs per year and time periods of up to 2 years may be requested for 
Phase II.  Total costs include direct costs, F&A, and fee/profit.

FUNDS AVAILABLE 

The NCI intends to commit approximately $1 million a year for two years to 
fund a total of two to five Phase I and/or Phase II applications under the 
SBIR/STTR set-aside funding mechanism. Although the financial plans of the 
NCI provide support for this program, awards pursuant to this RFA are 
contingent upon the availability of funds and the receipt of a sufficient 
number of meritorious applications. At this time, it is not known if 
competing renewal applications will be accepted and/or if this RFA will be 
reissued.

ELIGIBLE INSTITUTIONS:

Eligibility requirements are described in the SBIR/STTR Omnibus Solicitation.  
Only small business concerns are eligible to submit SBIR/STTR applications.  
A small business concern is one that, on the date of award for both Phase I 
and Phase II agreements, meets ALL of the criteria as described in the 
current SBIR/STTR Omnibus Solicitation.

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.  On an SBIR application, the principal 
investigator must have his/her primary employment (more than 50 percent) with 
the small business at the time of award and for the duration of the project. 
The PI on an STTR application may be employed with the small business concern 
or the participating non-profit research institution as long as s/he has a 
formal appointment with or commitment to the applicant small business 
concern, which is characterized by an official relationship between the small 
business concern and that individual. 

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 questions about scientific/research issues to:

Sudhir Srivastava, Ph.D., M.P.H.
Division of Cancer Prevention
National Cancer Institute
6130 Executive Boulevard, EPN Room 3144
Bethesda, MD 20892
Rockville, MD 20852 (for express/courier service)
Telephone:  (301) 496-3983
FAX:  (301) 402-8990
Email: ss1a@nih.gov

o Direct your questions about peer review issues to: 

Referral Officer
National Cancer Institute
Division of Extramural Activities
6116 Executive Boulevard, Room 8041, MSC 8329
Bethesda, MD 20892-8329
Rockville, MD 20852 (for express/courier service)
Telephone: (301) 496-3428
FAX: (301) 402-0275 
Email:  ncirefof@dea.nci.nih.gov

o Direct questions about financial or grants management matters to:

Shane Woodward
Grants Administration Branch
National Cancer Institute
Fairview Center Building, Suite 300
1003 West 7th St.
Frederick, MD 21701-4106
Telephone: (301) 846-1017
FAX: (301) 846-5720
Email:  woodwars@mail.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:

Sudhir Srivastava, Ph.D., M.P.H.
Division of Cancer Prevention
National Cancer Institute
6130 Executive Boulevard, EPN Room 3144
Bethesda, MD 20892
Rockville, MD 20852 (for express/courier service)
Telephone:  (301) 496-3983
FAX:  (301) 402-8990
Email: ss1a@nih.gov

SUBMITTING AN APPLICATION

The PHS 398 research grant application must be used for all SBIR/STTR Phase 
I, Phase II, and Fast-Track applications (new and revised).  Effective 
October 1, 2003, applications must have a Dun and Bradstreet (D&B) Data 
Universal Numbering System (DUNS) number as the Universal Identifier when 
applying for Federal grants or cooperative agreements. The DUNS number can be 
obtained by calling (866) 705-5711 or through the web site at 
http://www.dunandbradstreet.com/. The DUNS number should be entered on line 
11 of the face page of the PHS 398 form. The PHS 398 is available at 
http://grants.nih.gov/grants/funding/phs398/phs398.html.  Prepare your 
application in accordance with the SBIR/STTR Omnibus Solicitation and the PHS 
398. Helpful information for advice and preparation of the application can be 
obtained at http://grants.nih.gov/grants/funding/sbirgrantsmanship.pdf. The 
NIH will return applications that are not submitted on the 5/2001 version of 
the PHS 398.  For further assistance, contact GrantsInfo; Telephone: (301) 
435-0714; Email: GrantsInfo@nih.gov. 

SUPPLEMENTARY INSTRUCTIONS

Support for the second year will be contingent upon Institute programmatic 
evaluation to ensure that investigators are accomplishing the goals 
presented.

USING THE RFA LABEL:  The RFA label available in the PHS 398 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.  The RFA label is also available at 
http://grants.nih.gov/grants/funding/phs398/labels.doc or 
http://grants.nih.gov/grants/funding/phs398/labels.pdf. 

The title and number of this RFA must be typed on line 2 of the face page of 
the application and the YES box must be marked.

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)

To expedite the review process, at the time of submission, send two 
additional copies of the application and all five copies of the appendix 
materials to:  

Referral Officer
Division of Extramural Activities
National Cancer Institute
6116 Executive Boulevard, Room 8041, MSC 8329
Bethesda, MD  20892-8329
Rockville, MD  20852 (for express/courier service)

Appendices should be comprised of unbound materials, with separators between 
documents.

APPLICATIONS HAND-DELIVERED BY INDIVIDUALS TO THE NATIONAL CANCER INSTITUTE 
WILL NO LONGER BE ACCEPTED.  This policy does not apply to courier deliveries 
(i.e., FEDEX, UPS, DHL, etc.) 
(http://grants.nih.gov/grants/guide/notice-files/NOT-CA-02-002.html).  
This policy is similar to and consistent with the policy for applications 
addressed to Centers for Scientific Review as published in the NIH Guide 
Notice at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-012.html.

RECEIPT OF APPLICATIONS. Applications must be received on or before the 
receipt dates listed on the first page of this announcement. If an 
application is received after that date, it will be returned to the applicant 
without review.

Although there is no immediate acknowledgement of the receipt of an 
application, applicants are generally notified of the review and funding 
assignment within 8 weeks.

The Center for Scientific Research (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.  However, when a previously unfunded application, 
originally submitted as an investigator-initiated application, is to be 
submitted in response to an RFA, it is to be prepared as a NEW application.  
That is the application for the RFA must not include an Introduction 
describing the changes and improvements made, and the text must not be marked 
to indicate the changes from the previous unfunded version of the 
application.  

PEER REVIEW PROCESS

Upon receipt, applications will be reviewed for completeness by the CSR and 
responsiveness by the NCI.  Incomplete and/or non-responsive applications 
will not be reviewed.

Applications that are complete and responsive to the RFA will be evaluated 
for scientific and technical merit by an appropriate peer review group 
convened by the Division of Extramural Activities of the NCI in accordance 
with the review criteria stated below.  As part of the initial merit review, 
all applications will:

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 written critique
o Receive a second level review by the National Cancer Advisory Board.

REVIEW CRITERIA

The goals of NIH-supported research are to advance our understanding of 
biological systems, improve the control of disease, and enhance health.  In 
the written comments, reviewers will be asked to evaluate the application in 
order to judge the likelihood that the proposed research will have a 
substantial impact on the pursuit of these goals within the context of the 
SBIR/STTR Program.  The scientific review group will address and consider 
each of the following criteria in assigning the application’s overall score:

o Significance 
o Approach 
o Innovation
o Investigator
o Environment

ALL SBIR/STTR APPLICATIONS

1.  Significance:  Does the proposed project have commercial potential to 
lead to a marketable product or process? Does this study address an important 
problem? What may be the anticipated commercial and societal benefits of the 
proposed activity? If the aims of the application are achieved, how will 
scientific knowledge be advanced? Does the proposal lead to enabling 
technologies (e.g., instrumentation, software) for further discoveries? Will 
the technology have a competitive advantage over existing/alternate 
technologies that can meet the market needs? 

2.  Approach:  Are the conceptual framework, design, methods, and analyses 
adequately developed, well-integrated, and appropriate to the aims of the 
project? Is the proposed plan a sound approach for establishing technical and 
commercial feasibility? Does the applicant acknowledge potential problem 
areas and consider alternative strategies? Are the milestones and evaluation 
procedures appropriate? 

3.  Innovation:  Does the project challenge existing paradigms or employ 
novel technologies, approaches or methodologies? Are the aims original and 
innovative? 

4.  Investigators: Is the Principal Investigator capable of coordinating and 
managing the proposed SBIR/STTR? Is the work proposed appropriate to the 
experience level of the Principal Investigator and other researchers, 
including consultants and subcontractors (if any)? Are the relationships of 
the key personnel to the small business and to other institutions appropriate 
for the work proposed? 

5.  Environment:  Is there sufficient access to resources (e.g., equipment, 
facilities)? Does the scientific and technological environment in which the 
work will be done contribute to the probability of success? Do the proposed 
experiments take advantage of unique features of the scientific environment 
or employ useful collaborative arrangements? 

ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the following 
items will be considered in the determination of scientific merit and the 
priority score:

PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK: The involvement of human 
subjects and protections from research risk relating to their participation 
in the proposed research will be assessed. (See additional information and 
criteria included in the section on Federal Citations, below.)
 
INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH: 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 additional information and Inclusion Criteria in the sections 
on Federal Citations, below.)

Human Subjects:

1. Protection of Human Subjects from Research Risks - for all studies 
involving human subjects. See instructions and "Guidance for Preparing the 
Human Subjects Research Section.”  If an exemption is claimed, is it 
appropriate for the work proposed? If no exemption is claimed, are the 
applicant's responses to the six required points appropriate?  Are human 
subjects placed at risk by the proposed study? If so, are the risks 
reasonable in relation to the anticipated benefits to the subjects and 
others? Are the risks reasonable in relation to the importance of the 
knowledge that reasonably may be expected to be gained?  Are the plans 
proposed for the protection of human subjects adequate? 

2. Inclusion of Women Plan - for clinical research only.  Does the applicant 
propose a plan for the inclusion of both genders that will provide their 
appropriate representation? Does the applicant provide appropriate 
justification when representation is limited or absent? Does the applicant 
propose appropriate and acceptable plans for recruitment/outreach and 
retention of study participants? 

3. Inclusion of Minorities Plan - for clinical research only.  Does the 
applicant propose a plan for the inclusion of minorities that will provide 
their appropriate representation? Does the applicant provide appropriate 
justification when representation is limited or absent? Does the applicant 
propose appropriate and acceptable plans for recruitment/outreach and 
retention of study participants? 

4. Inclusion of Children Plan - for all studies involving human subjects.  
Does the applicant describe an acceptable plan in which the representation of 
children of all ages (under the age of 21 years) is scientifically 
appropriate and recruitment/retention is addressed realistically? If not, 
does the applicant provide an appropriate justification for their exclusion? 

5. Data and Safety Monitoring Plan - for clinical trials only.  Does the 
applicant describe a Data and Safety Monitoring Plan that defines the general 
structure of the monitoring entity and mechanisms for reporting Adverse 
Events to the NIH and the IRB? 

CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH: If vertebrate animals are to 
be used in the project, the required five items described under Vertebrate 
Animals (section f of the Research Plan instructions) will be assessed.  

BIOHAZARDS:  Is the use of materials or procedures that are potentially 
hazardous to research personnel and/or the environment proposed? Is the 
proposed protection adequate? 

ADDITIONAL REVIEW CONSIDERATIONS: The following items may be also be 
considered by reviewers but will not be included in the determination of 
scientific merit.

SHARING RESEARCH DATA:  Applicants requesting more than $500,000 in direct 
costs in any year of the proposed research must include a data sharing plan 
in their application. The reasonableness of the data sharing plan or the 
rationale for not sharing research data will be assessed by the reviewers. 
However, reviewers will not factor the proposed data sharing plan into the 
determination of scientific merit or priority score.

BUDGET:  The reasonableness of the proposed budget may be considered.  For 
all applications, is the percent effort listed for the PI appropriate for the 
work proposed? On applications requesting up to $100,000 total costs, is the 
overall budget realistic and justified in terms of the aims and methods 
proposed? On applications requesting over $100,000 in total costs, is each 
budget category realistic and justified in terms of the aims and methods? 

PERIOD OF SUPPORT: The appropriateness of the requested period of support in 
relation to the proposed research.

PHASE II APPLICATIONS 

In addition to the above review criteria:

1. How well did the applicant demonstrate progress toward meeting the Phase I 
objectives, demonstrating feasibility, and providing a solid foundation for 
the proposed Phase II activity? 

2. Did the applicant submit a concise Commercialization Plan that adequately 
addresses the seven areas described in the Research Plan item J? 

3. Does the project carry a high degree of commercial potential, as described 
in the Commercialization Plan? 

AMENDED APPLICATIONS

In addition to the above criteria, the following criteria will be applied to 
revised applications.

1. Are the responses to comments from the previous SRG review adequate? 

2. Are the improvements in the revised application appropriate? 

PHASE I/PHASE II FAST-TRACK APPLICATION REVIEW CRITERIA

For Phase I/Phase II Fast Track applications, the following criteria also 
will be applied:

1. Does the Phase I application specify clear, appropriate, measurable goals 
(milestones) that should be achieved prior to initiating Phase II? 

2. Did the applicant submit a concise Commercialization Plan that adequately 
addresses the seven areas described in the Research Plan, item J? 

3. To what extent was the applicant able to obtain letters of interest, 
additional funding commitments, and/or resources from the private sector or 
non-SBIR/ STTR funding sources that would enhance the likelihood for 
commercialization? 

4. Does the project carry a high degree of commercial potential, as described 
in the Commercialization Plan? 

Phase I and Phase II Fast-Track applications that satisfy all of the review 
criteria will receive a single rating. Failure to provide clear, measurable 
goals may be sufficient reason for the scientific review group to exclude the 
Phase II application from Fast-Track review.

RECEIPT AND REVIEW SCHEDULE

Letter-of Intent-Receipt Dates: January 17, 2005; May 16, 2005; September 14,
2005
Application Receipt Dates: February 14, 2005; June 13, 2005; October 12, 2005
Peer Review Dates: June/July 2005; October/November 2005; February/March 2006
Council Reviews: September 2005; February 2006; June 2006
Earliest Anticipated Start Dates:  January 1, 2006; April 2006; July 2006

AWARD CRITERIA

Applications submitted in response to an RFA will compete for available funds 
with all other recommended SBIR and STTR applications.  The following will be 
considered in making funding decisions:  

o Scientific merit of the proposed project as determined by peer review;
o Availability of funds; and 
o Relevance to program priorities.

For FAST-TRACK applications, the Phase II portion may not be funded until a 
Phase I final report and other documents necessary for continuation have been 
received and assessed by program staff that the Phase I milestones have been 
successfully achieved. 

REQUIRED FEDERAL CITATIONS 

HUMAN SUBJECTS PROTECTION: Federal regulations (45CFR46) require that 
applications and proposals involving human subjects must be evaluated with 
reference to the risks to the subjects, the adequacy of protection against 
these risks, the potential benefits of the research to the subjects and 
others, and the importance of the knowledge gained or to be gained. See 
http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm.

DATA AND SAFETY MONITORING PLAN: Data and safety monitoring is required for 
all types of clinical trials, including physiologic, toxicity, and dose-
finding studies (phase I); efficacy studies (phase II); and efficacy, 
effectiveness, and comparative trials (phase III).  The establishment of data 
and safety monitoring boards (DSMBs) is required for multi-site clinical 
trials involving interventions that entail potential risk to the 
participants.  (See NIH Policy for Data and Safety Monitoring, NIH Guide for 
Grants and Contracts, June 12, 1998, at 
http://grants.nih.gov/grants/guide/notice-files/not98-084.html.)

Clinical trials supported or performed by NCI require special considerations.  
The method and degree of monitoring should be commensurate with the degree of 
risk involved in participation and the size and complexity of the clinical 
trial.  Monitoring exists on a continuum from monitoring by the principal 
investigator/project manager or NCI program staff or a Data and Safety 
Monitoring Board (DSMB).  These monitoring activities are distinct from the 
requirement for study review and approval by an Institutional review Board 
(IRB).  For details about the Policy for the NCI for Data and Safety 
Monitoring of Clinical trials, see 
http://deainfo.nci.nih.gov/grantspolicies/datasafety.htm.  For Phase I and II 
clinical trials, investigators must submit a general description of the data 
and safety monitoring plan as part of the research application.  For 
additional information, see NIH Guide Notice on “Further Guidance on a Data 
and Safety Monitoring for Phase I and II Trials” at
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html.  
Information concerning essential elements of data safety monitoring plans for 
clinical trials funded by the NCI is available at  
http://www.cancer.gov/clinical_trials/.

SHARING RESEARCH DATA: Investigators submitting an NIH application seeking 
$500,000 or more in direct costs in any single year are expected to include a 
plan for data sharing (http://grants.nih.gov/grants/policy/data_sharing) or 
state why this is not possible. Investigators should seek guidance from their 
institutions, on issues related to institutional policies, local IRB rules, 
as well as local, state and Federal laws and regulations, including the 
Privacy Rule. Reviewers will consider the data sharing plan but will not 
factor the plan into the determination of the scientific merit or the 
priority score. 

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 "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. 

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.  A 
continuing education program in the protection of human participants in 
research is available online at http://cme.nci.nih.gov/.

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

Applicants may wish to place data collected under this PA 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.

STANDARDS FOR PRIVACY OF INDIVIDUALLY IDENTIFIABLE HEALTH INFORMATION
The Department of Health and Human Services (DHHS) issued final modification 
to the “Standards for Privacy of Individually Identifiable Health 
Information”, the “Privacy Rule,” on August 14, 2002.  The Privacy Rule is a 
federal regulation under the Health Insurance Portability and Accountability 
Act (HIPAA) of 1996 that governs the protection of individually identifiable 
health information, and is administered and enforced by the DHHS Office for 
Civil Rights (OCR).  

Decisions about applicability and implementation of the Privacy Rule reside 
with the researcher and his/her institution. The OCR website 
(http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including 
a complete Regulation Text and a set of decision tools on “Am I a covered 
entity?”  Information on the impact of the HIPAA Privacy Rule on NIH 
processes involving the review, funding, and progress monitoring of grants, 
cooperative agreements, and research contracts can be found at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.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.   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 at http://www.cfda.gov/ and is not subject to the 
intergovernmental review requirements of Executive Order 12372 or Health 
Systems Agency review.  Awards are made under the authorization of Sections 
301 and 405 of the Public Health Service Act as amended (42 USC 241 and 
284)and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. All 
awards are subject to the terms and conditions, cost principles, and other 
considerations described in the NIH Grants Policy Statement.  The NIH Grants 
Policy Statement can be found at 
http://grants.nih.gov/grants/policy/policy.htm. 

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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