CRANBERRY: URINARY TRACT INFECTION AND OTHER CONDITIONS 
 
RELEASE DATE:  February 21, 2003

RFA:  AT-03-004
 
National Center for Complementary and Alternative Medicine (NCCAM)
 (http://nccam.nih.gov/)
National Institute of Dental and Craniofacial Research (NIDCR) 
 (http://www.nidr.nih.gov/)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
 (http://www.niddk.nih.gov/)
Office of Dietary Supplements (ODS)
 (http://dietary-supplements.info.nih.gov/)

CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBERS:  93.213, 93.121, 93.849.
 
LETTER OF INTENT RECEIPT DATE:  April 22, 2003

APPLICATION RECEIPT DATE:  May 20, 2003

THIS RFA CONTAINS THE FOLLOWING INFORMATION

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

PURPOSE OF THIS RFA 

The purpose of this initiative is to support basic and clinical 
research on the role of cranberry (Vaccinium macrocarpon) in the 
prevention and treatment of urinary tract infections (UTI), other 
infections, and other conditions for which there is credible evidence 
of efficacy.  For clinical trials, preference will be given to those 
that also test mechanistic hypotheses.  This research may lead to 
definitive Phase III trials to determine the efficacy of cranberry in 
the prevention and/or treatment of UTI or other conditions.  Products 
of primary interest are (1) cranberry juice cocktail and (2) 
encapsulated powders, and their matching placebos. 
 
RESEARCH OBJECTIVES
 
Cranberry juice and to a lesser extent encapsulated powders have been 
used to prevent or treat UTI.  Preliminary evidence supports efficacy 
but the research suffers from major limitations.  Additional, but more 
limited, research of cranberry because of its inhibition of bacterial 
adhesion and antioxidant properties has been conducted for other 
infectious diseases and other conditions.  The appropriate product, 
dose, duration of intervention, and mechanism(s) of action are unknown 
or not clearly elucidated.  Finally, the nature and quality of 
previously studied cranberry products is not available in most of the 
published literature.  This limitation led NCCAM to award a contract 
for the development, preparation, characterization, standardization, 
and maintenance of a supply of research-grade cranberry products and 
matching placebos for use in NIH-sponsored clinical trials on 
cranberry.  These products will be available and are required for use 
by respondents to this RFA which seeks investigator-initiated basic and 
clinical research applications.
  
Significance

UTIs are a serious health problem affecting millions of people each 
year.  Infections of the urinary tract are common - only respiratory 
infections occur more often.  Each year, UTIs account for about seven 
million office visits and another one million emergency department 
visits, resulting in about 100,000 hospitalizations.  One woman in five 
develops a UTI during her lifetime; UTIs in men are less common.  
Nearly 20% of women who have a UTI will have another, and 30% of those 
will have yet another.  

Most infections arise from one type of bacteria, Escherichia coli, 
which normally live in the colon.  Usually, the most recent infection 
stems from a strain or type of bacteria that is different from the 
infection before it, indicating a separate infection.  (Even when 
several UTIs in a row are due to E. coli, slight differences in the 
bacterial strains indicate distinct infections.)  NIH-funded research 
suggests that one factor behind recurrent UTIs may be the ability of 
bacteria to attach to cells lining the urinary tract.  

Cranberry Use for UTI

Traditionally UTIs are treated with antibacterial drugs, but these are 
expensive, can have side effects, and may promote the emergence of 
drug-resistant bacteria.  Therefore, physicians suggest additional 
steps that patients can take on their own to avoid infection, including 
drinking cranberry juice 
(http://www.niddk.nih.gov/health/urolog/pubs/utiadult/utiadult.htm).  
 
Although cranberry juice is the form of cranberries most widely used, 
other cranberry products include cranberry powder in hard or soft 
gelatin capsules.  Market share data reported for 1999 and 2001 rank 
cranberry as number 10 and 9, respectively, among top-selling herbal 
products in the U.S. in the mainstream retail market 

Efficacy of Cranberry for UTI

The use of cranberry to prevent or treat UTI is common.  The 
accumulating evidence from small, non-controlled and controlled 
clinical trials suggests that cranberry may relieve symptoms associated 
with UTI and may reduce the need for antibiotics. The findings from the 
preliminary research provide reasons to support the conduct of small-
scale, focused clinical studies.

In 1998 (updated 2001), the Cochrane Library conducted separate reviews 
of cranberry for the prevention and treatment of UTI.   Each review 
used similar search strategies and selection criteria.  These included 
all randomized or quasi-randomized controlled trials.  Trials of at 
least one month and at least five days were included for prevention and 
treatment, respectively.  For prevention, four trials met the inclusion 
criteria.  For treatment, no trials meeting the inclusion criteria were 
found; only a few uncontrolled trials were found.  The Cochrane Library 
concluded that there was no good quality or reliable evidence of the 
effectiveness of cranberry juice or other cranberry products for the 
prevention or treatment of UTI and that more research is needed.

Three crossover studies (not included in either review) investigated 
the effect of cranberry on urine pH but did not attempt to assess 
activity in UTI.  Two of these three studies demonstrated a decrease in 
pH whereas the third study did not demonstrate a decrease in pH.  

Several other studies not included in the Cochrane reviews reported 
apparently contradictory results.  The first did not support the 
efficacy of cranberry in UTI in children with neurogenic bladder.  The 
second was a study of adults with spinal cord injury that demonstrated 
a reduction in biofilm load, but the importance of this effect for 
frank UTI was not determined.  A small study of urostomy patients also 
found equivocal results.  

Many of the clinical study reports available in the literature suffer 
from major limitations, as acknowledged in the Cochrane Library 
reviews.  Many trials have not been controlled or randomized, and 
randomization procedures have not always been described.  Crossover 
designs used in some studies may not be appropriate for studies of UTI.  
Other limitations include no blinding or failed blinding, lack of 
controlled diets or dietary assessment, use of convenience samples, and 
small numbers of subjects.  Sample sizes have ranged from as few as 10 
to as many as 192.  Trials have been faulted for the large number of 
dropouts/withdrawals which may be indicative that cranberry juice is 
not acceptable over the longer periods.  Intention-to-treat analyses 
were not often applied.  Most studies have been conducted in older or 
elderly patients.  Very few have been conducted in younger patients, 
with or without co-morbidities.  Primary outcomes have differed from 
study to study and have often included urinary pH, as well as rate of 
bacteriuria, biofilm load, and urinary white and red blood cell counts, 
rather than UTI.  Finally, the published articles do not describe the 
quality and character of the product.

Mechanism of Action for UTI

The mechanism of action of cranberry in treatment of UTI has not been 
clearly elucidated, but several potential hypotheses have been 
proposed.  

High levels of benzoic acid have been detected in cranberry juice, and 
until recently, it was suggested that the bacteriostatic effect of 
cranberry juice was due to acidification of the urine.  Several 
studies, however, have cast doubt on this mechanism.  

Current belief is that the prevention of UTI is achieved by inhibiting 
adhesion of the infecting bacteria, E. coli, to uroepithelial cells.  
Bacterial adherence to these cells is a critical step in the 
development of infection.  It is facilitated by fimbriae (proteinaceous 
fibers on the bacterial cell well).  Fimbriae produce adhesins which 
attach to receptors on uroepithelial cells.  It is hypothesized that 
cranberry constituents act by preventing adhesion.  Thus, the causative 
bacteria are flushed, preventing their colonization of the urinary 
tract.  In addition, there has been a report of the potential of 
cranberry juice to weaken attachment of E. coli to inert (nonliving) 
surfaces for control of biofilm formation on urinary catheters.    

Two components of cranberry juice have been shown to inhibit the 
adherence of E. coli to uroepithelial cells in vitro.  The first is 
fructose which may not survive absorption and metabolism intact to 
reach the urinary bladder.  The second is a group of polymeric 
proanthocyanidins; the chemical structures of three have been 
elucidated.  Fructose inhibits the adherence of type-1 fimbriated E. 
coli and proanthocyanidins inhibit the adherence of P-fimbriated E. 
coli to uroepithelial cells. 

Cranberry for Other Infections and Conditions

While much of the focus on the benefits of cranberry has been on UTI, 
cranberry could influence other conditions as well.  Examples of other 
areas of cranberry research follow.  These are for illustration only 
and are not meant to be exhaustive.  

Burger et al. reason that because cranberry has been shown to inhibit 
bacterial adhesion to uroepithelial cells, it may also be useful as 
antiadhesion therapy of Helicobacter pylori infections.  In a number of 
small in vitro studies, the investigators demonstrated that a high-
molecular-weight constituent of cranberry inhibits sialyllactose-
specific adhesion of H. pylori to a human gastric cell line and mucus, 
and to human erythrocytes.

Because of cranberry's purported antiadhesive properties, the effect of 
cranberry on the coaggregation of oral bacteria was tested.  A high-
molecular-weight nondialysable material was isolated from cranberry 
juice.  Although the molecular structure of this material and its 
mechanism of action are not known, in vitro studies showed that 
coaggregation of pairs of bacteria was inhibited and pilot in vivo 
studies showed that coaggregation of a large number of different pairs 
was reversed.  A small pilot study of individuals using a standard 
mouthwash which contained this high-molecular-weight constituent was 
conducted.  Results showed a reduction in colony forming units in 
saliva.  

Cranberry extracts may inhibit the oxidative modification of low-
density-lipoprotein (LDL) particles in a fashion similar to that of red 
wine and Concord grape juice as demonstrated in an in vitro study.  In 
vivo studies to evaluate the potential of cranberry to improve LDL 
antioxidant capacity have not been conducted.

Other areas of emerging preliminary data include the inhibition of 
breast cancer cells in animals, as well as the inhibition of certain 
strains of Haemophilus influenzae that is a common cause of ear and 
respiratory infections in children.
 
Safety

Cranberry taken orally in food amounts appears safe, although ingesting 
large amounts may result in diarrhea and other gastrointestinal 
symptoms.  Safety of amounts greater than that consumed in foods is 
unknown.  One study of cranberry tablets suggests caution for patients 
at risk for nephrolithiasis until safety of cranberry is confirmed.  
Currently, there is insufficient reliable information available to 
assess the interaction of cranberry with dietary supplements, 
medications, foods or laboratory tests.  

Cranberry Product

The dose, duration of intervention, and product characteristics 
necessary for efficacy in prevention or treatment of UTI are unknown.  
While cranberry juice cocktail is the most studied product, 
concentrates and encapsulated powders have also been used.  Some 
sources suggest six capsules of dried cranberry powder are equivalent 
to two fluid ounces cranberry juice cocktail.  The chemical composition 
of the study agents, in general, has not been described in the 
published literature, nor has the equivalence of the active 
constituents or markers among cocktails, concentrates, and 
capsules/tablets been described.  Therefore, comparison among study 
agents or trial results has not been possible.

The single-strength cranberry juice is highly acidic and astringent 
which makes it unpalatable.  Accordingly, the juice drink, i.e., 
cranberry juice cocktail, is a mixture of single-strength cranberry 
juice, sweetener, water, and vitamin C.  Cocktails are sweetened with 
fructose or artificially sweetened.  The percent of concentrate used in 
cocktails has ranged from about 25% to 80%, although cocktail with 33% 
pure juice is common. 

Cranberries contain about 88% water.  Among the other organic 
constituents are flavonoids, anthocyanins, catechin, triterpenoids, 
beta-hydroxybutyric acid, citric, malic, glucuronic, quinic and benzoic 
acids, ellagic acid, and vitamin C.  Quinic acid and the ratio of 
quinic acid to malic acid are reasonably constant and are used to 
calculate percentage of cranberry juice content in juice drinks and to 
assess cranberry juice authenticity.  Although anthocyanins change and 
degrade with processing and storage, the anthocyanin profile is unique 
to cranberry, and its qualitative pattern is characteristic.    

Doses of the cocktails used in studies have ranged from 160 to 750 ml a 
day, usually in divided doses at meals.  Intervention duration has also 
ranged from 5 days to 6 months (longer trials for prevention).  The 
rationale behind the amount and concentration of cranberry juice given 
to participants and the duration of intervention is usually not 
indicated.  

Related NIH-Supported Cranberry Projects

The NCCAM awarded a contract to support the preparation, 
characterization, standardization, and maintenance of a supply of 
research-grade cranberry products and matching placebos with 
concomitant quality control and quality assurance.  See the Request for 
Proposals for more detail:  http://nccam.nih.gov/research/
announcements/rfp/sow.pdf. These products will be used in 
NIH-supported basic and clinical research, which is 
responsive to this RFA, on the role of cranberry (Vaccinium 
macrocarpon) in the prevention and treatment of urinary tract 
infections (UTI), other infections, and other conditions for which 
there is credible evidence of efficacy.  Products developed by the 
contractor will be (1) cranberry juice cocktail and (2) encapsulated 
powders, and their matching placebos. 

Potential Research Directions

Although the objectives of this RFA are listed in the next section 
(Objectives of This Research Program), the published literature 
suggests that research directions might include, but not be limited to:

o Study the effect of cranberry in prevention of UTI and as adjunct to 
antibiotics in the treatment of UTI;

o Demonstrate whether cranberry reduces symptomatic UTI (primary 
endpoint being UTI; secondary endpoints being bacteriuria or pyuria);

o When justified, conduct randomized controlled trials of longer 
durations in a variety of patients with recurrent UTI;

o Determine the optimum amount of cranberry (dose-response), timing of 
ingestion, peak times to effect (temporal effect), variations in 
response;

o Assess adherence to study dosage and frequency requirements and 
participant retention;

o Assess the contribution of cranberry juice to increased fluid intake 
(concentrate vs. juice vs. other beverage) and the effect on UTI;

o Collect data systematically on adverse effects;

o Assess interactions with medications (such as antibiotics and H2 
blockers), dietary supplements, foods, and laboratory tests; 

o Evaluate relationship of cranberry/cranberry constituents to 
bacterial adherence;

o Evaluate relationship of cranberry/cranberry constituents and 
bacterial adherence to urinary pH;

o Study the absorption and distribution of marker compounds and key 
constituents of cranberry, such as the proanthocyanidins, to determine 
whether they achieve tissue and body fluid concentrations needed to 
inhibit bacterial adherence and other relevant biological endpoints;

o Investigate the antiadhesive property of cranberry/cranberry 
constituents on different strains of bacteria, as well as on various 
cellular substrates;

o Confirm/identify active agent(s) and/or other biochemical properties;

o Assess the equivalence of different cranberry products.

Objectives of This Research Program

Specifically, the objectives of this RFA are to: 

o Conduct laboratory studies to identify and test mechanisms that could 
explain the biological effects of cranberry/cranberry constituents;

o Study the basic mechanism(s) by which the constituents of cranberry 
block supra- or subgingival biofilm formation associated with dental 
caries, periodontal diseases or oral mucosal infections.  

o Determine pharmacodynamics and pharmacokinetics of 
cranberry/cranberry constituents in animal models and/or human 
subjects; and

o Conduct Phase I/II clinical studies to assess dose range effects, 
pharmacology, feasibility, safety, and biological efficacy of a 
cranberry products to justify subsequent, more definitive trials of 
their safety and efficacy.  (A Phase II study may be of modest size, 
provided it explores a range of dosages and is adequately powered to 
detect a meaningful difference between groups or validate surrogate 
markers of disease or clinical endpoints.) (Phase III studies will be 
considered not responsive to this RFA).

MECHANISM OF SUPPORT
 
This RFA will use NIH R01 and R21 award mechanisms.  As an applicant 
you will be solely responsible for planning, directing, and executing 
the proposed project.  This RFA is a one-time solicitation.  Future 
unsolicited, competing-continuation applications based on this project 
will compete with all investigator-initiated applications and will be 
reviewed according to the customary peer review procedures.  The 
anticipated award date is December 1, 2003.  Applications that are not 
funded in the competition described in this RFA may be resubmitted as 
NEW investigator-initiated applications using the standard receipt 
dates for NEW applications described in the instruction to the PHS 398 
application.

This RFA uses just-in-time concepts.  It also uses the modular as well 
as the non-modular budgeting formats (see 
http://grants.nih.gov/grants/funding/modular/modular.htm).  
Specifically, if you are submitting an application with direct costs in 
each year of $250,000 or less, use the modular format.  Otherwise 
follow the instructions for non-modular research grant applications.

FUNDS AVAILABLE 
 
The NIH intends to commit approximately $2.6 million in FY04 to fund 
five to 13 new and/or competitive continuation grants in response to 
this RFA. 

An R21 applicant may request a project period of up to two years with a 
combined budget for direct costs of up to $275,000 for the two-year 
period.

An R01 applicant may request a project period of up to four years and a 
budget of no more than $500,000 direct costs per year.  

Because the nature and scope of the proposed research will vary from 
application to application, it is anticipated that the size and 
duration of each award will also vary. Although the financial plans of 
the NCCAM, NIDCR, NIDDK, and ODS 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. 

Applicant institutions are strongly encouraged to discuss proposed 
projects with relevant NIH staff listed under INQUIRIES prior to 
submission.
 
ELIGIBLE INSTITUTIONS
 
You may submit (an) application(s) if your institution has any of the 
following characteristics:

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

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

SPECIAL REQUIREMENTS

This RFA seeks investigator-initiated basic and clinical research 
applications.  There is no common protocol.  However, special 
requirements are listed below.

o All grantees responsive to this RFA will be required to use the 
research-grade cranberry product(s) developed by a contractor.  
Therefore, the grant applicant is not responsible for the cost of the 
cranberry product(s).
  
Products developed by the contractor will be (1) cranberry juice 
cocktail and (2) encapsulated powders, and their matching placebos.  
The contractor will prepare, characterize, standardize, and maintain a 
supply of research-grade cranberry products and matching placebos with 
concomitant quality control and quality assurance.  It will provide 
(e.g., label, package, store, inventory, and distribute) the 
standardized cranberry products to the NIH-sponsored grantees 
responsive to this RFA.  The contractor will also provide the grantees 
with information about the proper dispensing, handling, and 
administration of the study agents.  See the Request for Proposals for 
more detail:  http://nccam.nih.gov/research/announcements/rfp/sow.pdf.

The contractor has been asked to provide cranberry products in batches 
to the grantees.   A one-year supply of cranberry juice cocktail will 
be delivered annually on or about June 1, 2004-2007.  A two-year supply 
of the supplement will be delivered on or about June 1, 2004 and 2006.    
For application purposes, grant applicants may plan their own study 
timelines; however, they should indicate their willingness to be 
flexible if their study agents are not available at the time they had 
originally planned.  The actual delivery dates and type and dose of 
products will be finalized in collaboration with the grantees, the 
contractor, and the NIH. 

o For only those applicants who intend to study single constituents 
isolated from the whole cranberry:  Studies that aim solely to 
identify/test a single chemical constituent of cranberry will not be 
supported by NCCAM under this RFA.  Studies in which single 
constituents are compared with the complex cranberry product are, 
however, appropriate.  For application purposes, these applicants will 
be responsible for the chemical isolation, characterization, quality 
and supply of the product for their own project.  After grant award, 
the NIH will negotiate with the contractor for the research-grade whole 
cranberry product to develop and provide the isolated constituent.  If 
successful in this negotiation, grant awards will be revised.

o All grantees are responsible for their own travel costs in about 
January 2004 (or earlier)to meet once in the Washington DC metropolitan 
area with the contractor providing the research-grade cranberry 
products and the NIH to determine study agent needs (agent type, 
dosing, quantities, labeling, packaging and delivery) and 
production/delivery schedules.  In addition, the contractor will 
conduct monthly conference calls (from about December 2003 through 
September 2004) with the grantees and the NIH. 

o Grantees conducting clinical studies are expected to file 
applications for Investigational New Drugs (IND) with the Food and Drug 
Administration (FDA) after award (tentatively prior to April 2004).  
However, contact with the FDA regarding FDA requirements and need for 
an IND would be appropriate prior to submission of the grant 
application to the NIH.

The contractor providing the research-grade cranberry products will be 
responsible for assisting the grantees by completing sections of the 
IND application.  The contractor will provide the following sections of 
the IND applications (referencing the Drug Master File may be 
appropriate) to the grantees by January 1, 2004:  (1) Investigator's 
Brochures for the cranberry products.  (2) Chemistry, manufacturing, 
and control information on the cranberry products.  (3) Pharmacology 
and toxicology data, if available.  (4) Previous human experience, 
including a list of the countries where the products are in clinical 
testing or have been approved or marketed, if appropriate.  The grantee 
will be responsible for all other sections.

[NOTE:  Under current regulations, any use in the United States of a 
drug product (e.g., well-characterized, therapeutic, biotechnology-
derived products) not previously authorized for marketing in the United 
States first requires submission of an IND to the FDA.  NIH grantees 
are required in the PHS 398 application to name the test article and 
state whether the 30-day interval between submission of applicant 
certification to the FDA and its response has elapsed or has been 
waived and/or whether use of the test article has been withheld or 
restricted by the FDA.  However, for purposes of this RFA, grant 
applicants are not expected to submit IND applications until after the 
grant award.] 

o Grantees conducting clinical trials must enter into a Clinical Trial 
Agreement.  Further information on NCCAM requirements for clinical 
trials are posted on the NCCAM website 
(http://nccam.nih.gov/research/policies/index.htm).  Clinical trials 
will be conducted under Good Clinical Practice (GCP) conditions as 
defined in the FDA document "E6 Good Clinical Practice:  Consolidated 
Guidance" (http://www.fda.gov/cder/guidance/959fnl.pdf).

o Applications for studies comparing cranberry product to a non-
cranberry product will not be considered responsive to this RFA and 
will be returned to the applicant without further consideration.

o Phase III studies will be considered not responsive to this RFA and 
will be returned to the applicant without further consideration.

o Applications requesting greater than $500,000 direct costs in any 
year will be considered not responsive to this RFA and will be returned 
to the applicant without further consideration.

WHERE TO SEND INQUIRIES

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

o Direct your questions about scientific/research issues to:

Marguerite Klein
Program Officer
Division Extramural Research and Training
National Center for Complementary and Alternative Medicine
Democracy 2, Suite 401
6707 Democracy Blvd.
Bethesda, MD  20892
Telephone:  (301) 402-5860
FAX:  (301) 480-3621
Email:  kleinm@mail.nih.gov

Dennis F. Mangan, Ph.D.
Division Basic and Translational Sciences
National Institute of Dental and Craniofacial Research
Building 45, Suite 18
Bethesda, MD  20892-6402
Telephone:  (301) 594-2421
FAX:  (301) 480-8318
Email:  Dennis.Mangan@nih.gov

Chris Mullins, Ph.D.
Director of Basic Cell Biology Programs
Division of Kidney, Urologic and Hematologic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
Democracy 2, Suite 637
6707 Democracy Blvd.
Bethesda, MD  20892
Telephone:  (301) 451-4902
FAX:  (301) 480-3510
Email:  mullinsc@extra.niddk.nih.gov

Joseph M. Betz, Ph.D.
Director, Dietary Supplements Methods and Reference Materials Program
Office of Dietary Supplements
6100 Executive Blvd., Room 3B01
Bethesda, MD  20892
Telephone:  (301) 435-2920
FAX:  (301) 480-1845
Email:  betzj@od.nih.gov

o Direct your questions about peer review issues to:

Dr. Martin Goldrosen
Director, Office of Scientific Review
National Center for Complementary and Alternative Medicine
Democracy 2, Suite 401
6707 Democracy Blvd.
Bethesda, MD  20892-5475
Telephone:  (301) 594-2014
FAX:  (301) 480-2419
Email:  goldrosm@mail.nih.gov

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

Victoria Carper
Grants Management Officer
National Center for Complementary and Alternative Medicine
Democracy 2, Suite 401
6707 Democracy Blvd.
Bethesda, MD  20892-5475
Telephone:  (301) 594-9102
FAX:  (301) 480-1552
Email:  vp8g@nih.gov

Mary Daley
Chief, Grants Management Officer
National Institute of Dental and Craniofacial Research
45 Center Drive, MSC 6402
Bldg. 45, Room 4AN-44B
Bethesda, MD  20892-6402
Telephone:  (301) 594-4808
FAX:  (301) 480-3562
Email:  md74u@nih.gov

Donna Huggins
Supervisory Grants Management Specialist
Grants Management Branch, DEA
National Institute of Diabetes and Digestive and Kidney Diseases
Democracy 2, Suite 711, MSC 5456
6707 Democracy Blvd.
Bethesda, MD  20892-5456
Telephone:  (301) 594-8848
FAX:  (301) 480-3504
Email:  Hugginsd@extra.niddk.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, consultants, collaborators
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:

Marguerite Klein
Program Officer
Division Extramural Research and Training
National Center for Complementary and Alternative Medicine
Democracy 2, Suite 401
6707 Democracy Blvd.
Bethesda, MD  20892
Telephone:  (301) 402-5860
FAX:  (301) 480-3621
Email:  kleinm@mail.nih.gov

SUBMITTING AN APPLICATION

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

SUPPLEMENTAL INSTRUCTIONS:  All instructions for the PHS 398 (rev. 
5/2001) must be followed, with these exceptions which apply to the R21 
exploratory/developmental grant only:

o Research Plan:  Items a – d of the Research Plan (Specific Aims, 
Background and Significance, Preliminary Studies, and Research Design 
and Methods) may not exceed a total of 15 pages.  No preliminary data 
is required but may be included if it is available.  

o Appendix:  Use the instructions for the appendix detailed in the PHS 
398 except that no more than five manuscripts accepted for publication 
may be included.

SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: Applications 
requesting up to $250,000 per year in direct costs must be submitted in 
a modular grant format.  The modular grant format simplifies the 
preparation of the budget in these applications by limiting the level 
of budgetary detail.  Applicants request direct costs in $25,000 
modules.  Section C of the research grant application instructions for 
the PHS 398 (rev. 5/2001) at 
http://grants.nih.gov/grants/funding/phs398/phs398.html includes step-
by-step guidance for preparing modular grants.  Additional information 
on modular grants is available at 
http://grants.nih.gov/grants/funding/modular/modular.htm.

For the R21 grant application, you may request direct costs in $25,000 
modules, up to a total direct cost of $275,000 for the combined two-
year award period.

USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 
5/2001) application form must be affixed to the bottom of the face page 
of the application.  Type the RFA number on the label.  Failure to use 
this label could result in delayed processing of the application such 
that it may not reach the review committee in time for review.  In 
addition, the RFA title and number must be typed on line 2 of the face 
page of the application form and the YES box must be marked. The RFA 
label is also available at: 
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf.
 
SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten 
original of the application, including the Checklist and appendices, 
and three signed, photocopies (including appendices), 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. Martin Goldrosen
Director, Office of Scientific Review
National Center for Complementary and Alternative Medicine
Democracy 2, Suite 401
6707 Democracy Blvd. 
Bethesda, MD  20892-5475
Telephone:  (301) 594-2014
FAX:  (301) 480-2419
Email:  goldrosm@mail.nih.gov
 
APPLICATION PROCESSING: Applications must be received on or before 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.

Although there is no immediate acknowledgement of the receipt of an 
application, applicants are generally notified of the review and 
funding assignment within eight weeks.
 
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.  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.  While the investigator may 
still benefit from the previous review, the RFA application is not to 
state explicitly how.

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

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

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

The R21 exploratory/developmental grant is a mechanism for exploring 
the feasibility, as well as the development, of research projects and 
for generation of preliminary data. The R21 mechanism is specifically 
intended to support innovative ideas where preliminary data as evidence 
of feasibility are sparse or do not exist. These grants are not 
intended for large-scale undertakings or to support or
supplement ongoing research. Rather, R21 grants are intended to serve 
as a basis for planning and strengthening future research project grant 
applications(R01). It is important to note that, while originality 
(innovation) of approach and potential significance of the proposed 
research are major considerations in evaluation of R21 grant 
applications, the applicant is responsible for presenting the 
background literature that provides some basis for the approach and for 
developing a rigorous research plan.  Because the research plan is 
limited to 15 pages, an exploratory/developmental grant application 
need not have as much background material or preliminary information as 
one might normally expect in an R01 application.  Accordingly, 
reviewers will focus their evaluation on the conceptual framework, the 
level of innovation, and the potential to significantly advance our 
knowledge or understanding.  Appropriate justification for the proposed 
work can be provided through literature citations, data from other 
sources, or from investigator-generated data.  Preliminary data are not 
required but should be presented if available.  

The goals of NIH-supported research are to advance our understanding of 
biological systems, improve the control of disease, and enhance health.  
In the written comments, reviewers will be asked to discuss the 
following aspects of your application in order to judge the likelihood 
that the proposed research will have a substantial impact on the 
pursuit of these goals: 

o Significance 
o Approach 
o Innovation
o Investigator
o Environment
  
The scientific review group will address and consider each of these 
criteria in assigning your application's overall score, weighting them 
as appropriate for each application.  Your application does not need to 
be strong in all categories to be judged likely to have major 
scientific impact and thus deserve a high priority score.  For example, 
an investigator may propose to carry out important work that by its 
nature is not innovative but is essential to move a field forward.

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

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

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

INVESTIGATOR: Is the investigator appropriately trained and well suited 
to carry out this work? Is the work proposed appropriate to the 
experience level of the principal investigator and other researchers 
(if any)?

ENVIRONMENT: Does the scientific environment in which the work will be 
done contribute to the probability of success? Do the proposed 
experiments take advantage of unique features of the scientific 
environment or employ useful collaborative arrangements? Is there 
evidence of institutional support?  

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 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 Inclusion Criteria in the 
sections on Federal Citations, below).

CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH: If vertebrate animals 
are to be used in the project, the five items described under Section f 
of the PHS 398 research grant application instructions (rev. 5/2001) 
will be assessed.  

ADDITIONAL CONSIDERATIONS

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

RECEIPT AND REVIEW SCHEDULE

Letter of Intent Receipt Date:  April 22, 2002
Application Receipt Date:  May 20, 2003
Peer Review Date:  September-October, 2003
Council Review:  November, 2003
Earliest Anticipated Start Date:  December 1, 2003

AWARD CRITERIA

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

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

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.

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

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

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

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN 
SUBJECTS: The NIH maintains a policy that children (i.e., individuals 
under the age of 21) must be included in all human subjects research, 
conducted or supported by the NIH, unless there are scientific and 
ethical reasons not to include them. This policy applies to all initial 
(Type 1) applications submitted for receipt dates after October 1, 1998.

All investigators proposing research involving human subjects should 
read the "NIH Policy and Guidelines" on the inclusion of children as 
participants in research involving human subjects that is available at 
http://grants.nih.gov/grants/funding/children/children.htm. 

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

HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of 
research on hESCs can be found at 
http://grants.nih.gov/grants/stem_cells.htm and at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html.  
Only research using hESC lines that are registered in the NIH Human 
Embryonic Stem Cell Registry will be eligible for Federal funding (see 
http://escr.nih.gov).   It is the responsibility of the applicant to 
provide the official NIH identifier(s)for the hESC line(s)to be used in 
the proposed research.  Applications that do not provide this 
information will be returned without review. 

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.

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 ODS was mandated by Congress in 1994 and established with the 
Office of the Director, NIH.  The Dietary Supplement Health and 
Education Act (SHEA) [Public Law 103-417, Section 3.a] amended the 
Federal Food, Drug, and Cosmetic Act "to establish standards with 
respect to dietary supplements."  This law authorized the establishment 
of the ODS.

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.

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