MEDICATIONS DEVELOPMENT TO TREAT ALCOHOLISM (SBIR/STTR)

RELEASE DATE:  December 4, 2003

RFA Number:  RFA-AA-04-002 (This RFA has been reissued, see RFA-AA-06-006
                            and RFA-AA-06-007)

Department of Health and Human Services (DHHS)

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

COMPONENT OF PARTICIPATING ORGANIZATION:
National Institute of Alcohol Abuse and Alcoholism (NIAAA) 
 (http://www.niaaa.nih.gov) 

CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER: 93.273

LETTER OF INTENT RECEIPT DATE: March 15, 2004
APPLICATION RECEIPT DATE: April 14, 2004

THIS RFA CONTAINS THE FOLLOWING INFORMATION 

o Purpose of this RFA
o Research Objectives
o Mechanism(s) 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
o References

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) AND 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 following exceptions: 

o Application Receipt Date April 14, 2004
o Initial review convened by the NIAAA Division of Extramural Activities    
 
PURPOSE OF THIS RFA

The National Institute on Alcohol Abuse and Alcoholism (NIAAA) is 
seeking research grant applications on the development of medications 
for alcohol abuse/dependence and alcohol-related diseases. 
Investigations are needed on pharmacological agents that prevent or 
reduce alcohol intake by decreasing the alcohol craving/urge to drink 
and/or alleviating the negative symptoms associated with drinking 
cessation(e.g., protracted withdrawal syndrome). Applications are also 
encouraged to develop and test agents for the treatment of acute 
alcohol withdrawal and alcohol intoxication.  Evaluations of 
pharmacological agents to treat alcohol-induced diseases, such as 
alcoholic liver diseases, are encouraged as well. 

RESEARCH OBJECTIVES

Background

During the past decade advances have been made in medications 
development to treat alcoholism (see comprehensive reviews by Garbutt 
et al., 1999; Swift, 1999; and Kranzler, 2000). The fruits of these 
efforts have been highlighted by the FDA approval of naltrexone, the 
first medication approved for alcoholism in the 50 years since the 
introduction of disulfiram. Advances have also been made in 
understanding the biological mechanisms underlying alcohol drinking. 
For example, it is now known that multiple neurotransmitter, 
neuromodulator, and hormonal systems can alter alcohol intake and are 
either directly or indirectly involved in problematic drinking. These 
include opioid, serotonin, dopamine, gamma-aminobutyric acid (GABA), 
glutamate, neuropeptide Y (NPY), cannabinoid, and hypothalamic-
pituitary-adrenal (HPA) systems (Litten et al., 1996; Roberts and Koob, 
1997; Johnson and Ait-Daoud, 2000;). This recent knowledge has led to 
many biological targets for testing novel pharmacological agents. 

To date, the two most promising and successful medications are 
naltrexone and acamprosate. Two important clinical trials of naltrexone 
(Volpicelli et al., 1992 and O'Malley et al., 1992) first demonstrated 
efficacy of naltrexone in alcohol dependent patients and contributed 
significantly to FDA approval of naltrexone. Although naltrexone is not 
a "magic bullet" for alcoholism treatment, it appears to have a 
moderate effect in reducing drinking, particularly reducing relapse to 
heavy drinking (Volpicelli et al., 1997; Anton et al., 1999; Morris et 
al., 2001; Heinala et al., 2001). Recent studies have suggested that 
patient compliance plays a significant role in the efficacy of 
naltrexone (Volpicelli et al., 1997; Chick et al., 2000; Monti et al., 
2001). Nonetheless, naltrexone may not be effective for all alcoholics 
(Kranzler et al., 2000; Krystal et al, 2001). Several studies are 
currently being funded to address issues surrounding the clinical 
use of naltrexone such as how long should patients receive naltrexone; 
what is the optimal dose; what types of alcoholics respond best; what 
is the optimal combination with behavioral/psychosocial interventions; 
and can the efficacy of naltrexone be improved by combining it with 
other medications. Finally, nalmefene, another opioid antagonist, has 
also demonstrated effectiveness in preventing relapse to heavy drinking 
in alcohol- dependent patients (Mason et al., 1999). 

Acamprosate has been studied extensively in Europe and is currently 
approved for alcoholism treatment in 37 countries. Sixteen controlled 
clinical trials have been conducted across 11 European countries 
involving more than 4,600 alcohol dependent patients. The studies have 
consistently shown that individuals treated with acamprosate are more 
likely to complete treatment, have longer times to their first drink, 
have greater abstinence rates, and demonstrate longer cumulative 
abstinence durations than placebo-treated patients (Mason and Ownby, 
2000). Acamprosate's mechanism of action has yet to be definitively 
identified, although several studies suggest that it may modulate 
activity of the glutamate system (Littleton, 1995; Spanagel and 
Zieglgansberger, 1997). 

The serotonergic system has also been implicated in drinking behavior. 
The serontonin3 (5-HT3) receptor has been shown to regulate release of 
dopamine in the mesolimbic area, particularly in the nucleus accumbens. 
Ondansetron, a 5-HT3 antagonist, has been demonstrated to reduce desire 
to drink in humans and to augment stimulant and sedative effects of 
alcohol (Johnson et al., 1993; Swift et al., 1996). A 12-week dosage 
trial of ondansetron has recently been completed in early onset 
alcoholics and late onset alcoholics (Johnson et al., 2000b). 
Ondansetron reduced frequency and quantity of alcohol consumption in 
early onset alcoholics, but not in the late onset alcoholics. 
Interestingly, a preliminary study combining ondansetron and naltrexone 
showed that the combination reduced alcohol craving and enhanced 
drinking outcome to a greater extent than had each demonstrated alone 
(Johnson et al., 2000a; Ait-Daoud et al., 2001). 

Results of selective serotonin reuptake inhibitors (SSRIs) in human 
alcohol trials have been inconsistent (Pettinati, 1996, Kranzler, 
2000). Recent data, however, suggest that subpopulations of alcohol 
dependent patients respond differentially to the SSRIs. For example, 
Kranzler et al. (1996) and Pettinati et al. (2000) showed that higher-
risk/severity type B alcoholics had less favorable treatment outcome to 
SSRIs than lower-risk/severity type A alcoholics. Cornelius et al. 
(1997) found that fluoxetine reduced depressive symptoms and 
alcohol intake in severe inpatient populations of alcoholics with major 
depression and suicide risk. In contrast, Pettinati et al. (2001) and 
McGrath (1998) reported that fluoxetine and sertraline were no better 
than placebo in improving depression and reducing drinking in a less 
severe population of depressed alcoholics. 

Since all medications discussed above produce small to medium 
effects in reducing or preventing drinking, development and evaluation 
of new and more potent medications remains a high priority. Several 
promising pharmacological agents could lead to clinical testing. These 
include, but are not limited to, memantine, a non-competitive NMDA 
antagonist (Holter et al., 1996); kudzu and its purified active 
components (e.g., puerarin) (Keung and Vallee, 1993; Lin et al., 1996); 
corticotropin-releasing factor (CRF) antagonists (Bell et al., 1998; Le 
et al., 2000; Richter et al., 2000); opioid subtype receptor 
antagonists such as delta2 antagonist naltriben (June et al., 1999); 6-
beta naltrexol, an active metabolite of naltrexone (Rukstalis et al., 
2000); synthetic neurosteroids (Morrow et al., 1999); 1-
aminocyclopropanecarboxylic acid (ACPC), a NMDA partial agonist 
(Stromberg et al., 1999); FG 5974 (and its analogues), a 5-HT1A 
agonist/5-HT2A antagonist (Roberts et al., 1998), and agents with 
selective affinity to GABAA alpha1 or GABAA alpha5 receptor subunits 
(June et al., 2001, Harvey et al., 2002). 

A spectrum of neurotransmitter systems (e.g., GABA, NMDA, 5-HT, 
dopamine), neuropeptide systems (neuropeptide Y, leptin), signal 
transduction pathways (PKA, PKC), and gene transcription factors (delta 
fosB) have been implicated in alcohol dependence and craving.  New 
therapeutic compounds may emerge from further research on known ethanol 
targets, or may occur by identifying possible therapeutic targets and 
prototype drug candidates through research on systems and mechanisms 
not yet examined in relation to alcohol.  As basic research reveals 
promising targets relevant to alcohol abuse and its consequences, 
analogs acquired from existing libraries, or newly-synthesized analogs 
developed through computational and combinatorial chemistry can be 
screened in vitro or in standardized behavioral assays for potential 
therapeutic efficacy.

Advances in molecular genetics (e.g., microarray analysis, targeted 
mutations, and proteomics) offer a powerful approach for broad-spectrum 
scanning of participants in the adaptive process.  Individual gene 
clusters or functionally-related proteins can be identified in specific 
brain regions in temporal relation to alcohol exposure.  Such studies 
may identify biochemical pathways and brain circuits which are 
preferentially recruited as alcohol dependence develops.  Receptors or 
pathways involved in alcohol drinking and other alcohol effects can be 
disabled selectively with targeted knockout strategies. An unanswered 
question facing medical treatment concerns potential targets for 
modifying neurological changes underlying craving and alcohol-seeking 
after periods of prolonged abstinence.

For pharmacological management of acute alcohol withdrawal, 
benzodiazepines have been the most widely used medication over the past 
two decades. They have consistently been demonstrated to assuage many 
symptoms of withdrawal (Mayo-Smith, 1997). Recent studies have focused 
on benzodiazepine dosing strategies. For example, a "loading dose" 
technique in which benzodiazepines are given every 1 or 2 hours until 
withdrawal symptoms subside, appears effective in preventing over- and 
under-dosing of medication (Wartenberg et al., 1990; Sullivan et al., 
1991; Saitz et al., 1994). Yet in spite of their benefits, 
benzodiazepines have adverse effects including memory impairment, 
drowsiness, lethargy, and cognitive problems. 

Finally, progress has been made in elucidating the mechanisms of 
alcohol-induced organ damage. In particular, several primary factors 
underlying the pathogensis of alcoholic liver disease have been 
identified including cytokines and reactive oxygen species (ROS) 
(Tsukamoto and Lu, 2001). For example, the administration of antibodies 
against the proinflammatory tumor necrosis factor (TNF ?) attenuated 
alcohol-induced liver injury in rats (Iimuro et al., 1997). A later 
study showed an absence of alcohol liver injury in knockout mice 
missing the TNF receptor 1 (Yin et al., 1999). ROS are generated by the 
metabolism of alcohol and can also cause damage to the liver (Tsukamoto 
and Lu, 2001). ROS are quickly inactivated by antioxidants, such as 
glutathione and vitamins A and E. Antioxidants, such as S-adenosyl-L- 
methionine (SAMe), have also been shown to reduce alcohol-induced liver 
injury in animals. Potential new treatments of alcoholic liver disease 
include antioxidants, such as SAMe and vitamin E; as well as other 
types of agents including phosphatidylcholine, a phospholipid; 
pirfenidone, a new broad- spectrum anti-fibrotic agent; and metformin, 
an insulin-sensitizing agent (Lieber, 2001; Miric et al., 2001; 
Tsukamoto and Lu, 2001).  

SPECIFIC AREAS OF INTEREST BUT NOT LIMITED TO

NIAAA is committed to the development and assessment of pharmacological 
agents to treat alcohol use disorders as well as the more prevalent and 
severe medical conditions associated with chronic drinking. 
Pharmacological agents of interest can be categorized by function as 
follows: 

- Agents to decrease craving or urge to drink. 

- Agents to diminish drinking by alleviating co-occurring psychiatric 
pathology and other drug use.

- Agents to treat alcohol-associated liver disease and other end-organ 
diseases, such as pancreatitis, cardiomyopathy, and bone disease. 

- Agents to treat acute alcohol withdrawal.

- Agents to induce sobriety in intoxicated individuals

Many important clinical priorities and issues exist for these classes 
of pharmacological agents and are identified, but not limited, to the 
following: 

- New and existing pharmacological agents and combinations of those 
agents, need to be identified and evaluated in conjunction with 
behavioral therapies for alcoholism treatment. Optimal dosing regimens 
and length of treatment need to be established. Although NIAAA has 
supported projects on the efficacy of the opioid antagonist naltrexone, 
the therapeutic potential of other pharmacological agents in the opioid 
class is a current research priority. In addition to opioid 
antagonists, the therapeutic potential of other types of agents needs 
to be assessed. Among these are agents that interact with the 
serotonergic, dopaminergic, glutamatergic, GABAergic, NPY, cannabinoid, 
and HPA systems as well as herbal preparations.

- Development of pharmacological agents to attenuate negative symptoms 
of chronic drinking, sometimes referred to as the "protracted 
withdrawal" syndrome. Research on potential pharmacological treatment 
of this phenomenon has been quite limited, due to failure to specify 
cardinal symptoms associated with sustained sobriety by alcoholics. 
Research is needed to establish operational definitions of this event 
as is research on agents to reduce the severity of protracted symptoms. 

-Factors influencing clinical efficacy of medications to treat alcohol 
abuse and dependence can be identified using human laboratory 
behavioral pharmacology paradigms. Prior to beginning phase 2 clinical 
trials, potential medications can be screened in the laboratory to 
determine the following: 1) the medication's impact to reduce craving 
for alcohol and/or to diminish the negative symptoms of drinking; 2) 
likelihood of adverse events, especially in the presence of alcohol; 3) 
pharmacokinetics for medication combinations; and 4) optimal dosing 
regimens. Studies are sought which develop and expand use of these 
human laboratory paradigms. 

- Development of medications to treat alcoholic liver diseases and 
other alcohol-related, end-organ diseases. These may include agents 
that inactivate excess ROS or alter the production or clearance of 
cytokines. In reducing the high mortality from alcoholic hepatitis and 
cirrhosis, potential medications that prevent necrosis/inflammation and 
avert or reverse the progression of fibrosis are of high priority. 
Other potential agents include those that are effective in treating 
alcohol-induced portal hypertension, pancreatitis, and bone disease. 

- Use of proteomic approaches to identify molecular targets for 
medications development for alcohol abuse susceptibility, alcohol 
dependence, alcohol consumption, withdrawal, and relapse, and alcohol-
associated medical conditions.

- Synthesis of new compounds based on the molecular structure of 
receptors, ion channels, and sites of cellular signal transduction 
mechanisms involved in alcohol's actions on the nervous system.

- Screening of existing "off the shelf" compounds for properties 
associated with therapeutic efficacy for treating alcohol abuse and 
alcohol related conditions.

- Development of alternative medications to treat acute alcohol 
withdrawal.  Also, assuming the "kindling" effect (the severity of 
withdrawal symptoms increases after repeated withdrawal episodes) has 
clinical relevance (Becker, 1998), can kindling be effectively curbed 
by medications to treat withdrawal? 

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 
September 27, 2004. 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.  

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_2001/part_i_1.htm. 

Except as otherwise stated in this RFA, awards will be administered 
under NIH grants policy as stated in the NIH Grants Policy Statement, 
March 2001, available at 
http://grants.nih.gov/grants/policy/nihgps_2001.  

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.  The 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.  However, these award levels for time and amount 
are statutory guidelines, not ceilings.  Therefore, applicants are 
encouraged to propose a reasonable budget and project period that is 
appropriate for completion of the research project.  Deviations from 
the guidelines are acceptable, but must be well justified.  Applicants 
are encouraged to discuss budgetary deviations with NIH program staff 
prior to submission of the application.  For this RFA, time periods of 
up to 2 years for Phase I may be requested.  Time periods of up to 3 
years may be requested for Phase II.  Total costs include direct costs, 
F&A, and fee/profit.  

FUNDS AVAILABLE 

NIAAA intends to commit approximately $2,000,000 to fund 5-10 Phase I 
and/or Phase II applications under the SBIR/STTR set-aside funding 
mechanism. Although the financial plans of the NIAAA 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%) 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. 

SPECIAL REQUIREMENTS

All applications that list direct costs greater than $500,000 in any 
year of the proposed research must have a data sharing plan. 
Information on NIH data sharing policy and procedures can be found at:  
http://grants.nih.gov/grants/policy/data_sharing/index.htm

WHERE TO SEND INQUIRIES

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

o Direct your questions about scientific/research issues to:

NIAAA Program Contacts:

Joanne B. Fertig, Ph.D.
Division of Treatment and Recovery Research
National Institute on Alcohol Abuse and Alcoholism
6000 Executive Boulevard, Suite 505 
Bethesda, MD 20892-7003
[For express mail use, Rockville, MD 20852]
Tel: (301) 443-0635
Fax: (301) 443-8774
Email: jfertig@niaaa.nih.gov

Peter B. Silverman, Ph.D., J.D.
Division of Neuroscience and Behavior
National Institute on Alcohol Abuse and Alcoholism
6000 Executive Boulevard, Suite 402
Bethesda, MD 20892-7003 
[for express mail, use Rockville, MD 20852]
Tel. 301-402-6966   
FAX  301-594-0673
Email: psilverm@mail.nih.gov

o Direct your questions about peer review issues to:

Eugene G. Hayunga, Ph.D.
Chief, Extramural Project Review Branch
Office of Scientific Affairs 
National Institute on Alcohol Abuse and Alcoholism 
6000 Executive Boulevard, Room 409, MSC 7003 
Bethesda, MD 20892-7003 
Rockville, MD 20852 (for express/courier service) 
Telephone: (301) 443-4375
FAX: (301) 443-6077

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

Judy Fox (formerly Simons)
Chief, Grants Management Branch
Office of Planning and Resource Management
National Institute on Alcohol Abuse and Alcoholism
Willco Building, Suite 504
6000 Executive Boulevard, MSC 7003
Bethesda, MD 20892-7003
[for express mail, use Rockville, MD 20852]
Tel. (301) 443-4704
Fax  (301) 443-3891
email:  jsimons@willco.niaaa.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 affect the review of a subsequent application, the information that 
it contains allows NIAAA 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: 

Extramural Project Review Branch
Office of Scientific Affairs 
ATTN: RFA-AA-04-002
National Institute on Alcohol Abuse and Alcoholism 
6000 Executive Boulevard, Room 409, MSC 7003 
Bethesda, MD 20892-7003 
Rockville, MD 20852 (for express/courier service) 
Telephone: (301) 443-4375 
FAX: (301) 443-6077 

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. 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. 

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.  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/labels.doc or 
http://grants.nih.gov/grants/funding/phs398/labels.pdf. 

SENDING AN APPLICATION TO THE NIH: 

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

Center for Scientific Review 
National Institutes of Health 
6701 Rockledge Drive, Room 1040, MSC 7710
Bethesda, MD 20892-7710 (for USPS EXPRESS OR REGULAR MAIL) 
Bethesda, MD 20817 (for EXPRESS/COURIER NON-USPS SERVICE) 

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

Extramural Project Review Branch 
Office of Scientific Affairs 
Attn: RFA-AA-04-002
National Institute on Alcohol Abuse and Alcoholism 
6000 Executive Blvd., Suite 409 
Bethesda, 20892-7003
[for express mail use Rockville, 20852] 
Telephone: (301) 443-4375 
Fax: (301) 443-6077 

RECEIPT OF APPLICATIONS. Applications must be received on or before the 
receipt date 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 NIAAA. Incomplete applications will not be 
reviewed. 
 
If the application is not responsive to the RFA, NIH staff may contact 
the applicant to determine whether to return the application to the 
applicant or submit it for review in competition with unsolicited 
applications at the next appropriate NIH review cycle.

Applications that are complete and responsive to the RFA will be 
evaluated for scientific and technical merit by an appropriate peer 
review group convened by the NIAAA 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 NIAAA National Advisory Council 
or 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? 

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: 

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? 

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? 

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? 

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) is 
scientifically appropriate and recruitment/retention is addressed 
realistically? If not, does the applicant provide an appropriate 
justification for their exclusion? 

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. If vertebrate animals are involved, are adequate plans 
proposed for their care and use? Are the applicant's responses to the 
five required points appropriate? Will the procedures be limited to 
those that are unavoidable in the conduct of scientifically sound 
research? 

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. Information on NIH data sharing policy and 
procedures can be found at:  
http://grants.nih.gov/grants/policy/data_sharing/index.htm

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:

- 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? 
- Did the applicant submit a concise Commercialization Plan [formerly 
Product Development Plan] that adequately addresses the seven areas 
described in the Research Plan item J? 
- 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.

- Are the responses to comments from the previous SRG review adequate? 
- Are the improvements in the revised application appropriate? 

TYPE 2 PHASE II COMPETING CONTINUATION APPLICATIONS 

In addition to the above review criteria, the following items will be 
applied to ALL Type 2 Competing Continuation Phase II applications in 
the determination of scientific merit and the priority score:

o  Does the activity as proposed address issues related to Federal 
regulatory approval processes?

o  What will be the effect of these studies on the concepts or methods 
that drive this field?

PHASE I/PHASE II FAST-TRACK APPLICATION REVIEW CRITERIA

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

- Does the Phase I application specify clear, appropriate, measurable 
goals (milestones) that should be achieved prior to initiating Phase II? 
- Did the applicant submit a concise Commercialization Plan [formerly 
Product Development Plan] that adequately addresses the seven areas 
described in the Research Plan, item J? 
- 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? 
- 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 Date:  March 15, 2004
Application Receipt Date:  April 14, 2004
Peer Review Date:  June/July 2004
Council Review:  September 2004
Earliest Anticipated Start Date:  September 27, 2004

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 
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.  
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); 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.  (NIH Policy for Data and Safety Monitoring, NIH 
Guide for Grants and Contracts, June 12, 1998: 
http://grants.nih.gov/grants/guide/notice-files/not98-084.html).  

SHARING RESEARCH DATA: Starting with the October 1, 2003 receipt date, 
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 or state why this is not possible. 
http://grants.nih.gov/grants/policy/data_sharing. 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. 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://stemcells.nih.gov/index.asp 
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, in the project description and elsewhere in the 
application as appropriate, 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 RFA in a public 
archive, which can provide protections for the data and manage the 
distribution for an indefinite period of time.  If so, the application 
should include a description of the archiving plan in the study design 
and include information about this in the budget justification section 
of the application. In addition, applicants should think about how to 
structure informed consent statements and other human subjects 
procedures given the potential for wider use of data collected under 
this award.

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). 
Those who must comply with the Privacy Rule (classified under the Rule 
as “covered entities”) must do so by April 14, 2003 (with the exception 
of small health plans which have an extra year to comply).  

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.

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