MEDICATIONS DEVELOPMENT TO TREAT ALCOHOLISM AND ALCOHOL-RELATED DISEASES (SBIR/STTR) RELEASE DATE: October 7, 2002 RFA NUMBER: AA-03-005 National Institute on Alcohol Abuse and Alcoholism (NIAAA) ( LETTER OF INTENT RECEIPT DATE: December 23, 2002 APPLICATION RECEIPT DATE: January 23, 2003 THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanism of Support o Mechanism Objectives 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 Peer Review Process o Review Criteria o Receipt and Review Schedule o Award Criteria o Required Federal Citations o References PURPOSE 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 (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 behavior. 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; Lallemand et al., 2001). 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 many 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). A 21-site trial of acamprosate has recently been completed in the US with 601 alcohol dependent patients. Results of this trial have been submitted to the FDA as part of a New Drug Application to obtain US approval. 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, 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 and colleagues (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 the medications discussed above produce small to medium effects to reduce or prevent drinking, developing and evaluating new and more potent medications remain 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 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 attenuate negative symptoms of alcoholism (e.g.,"protracted withdrawal" symptoms). - 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 combination 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 therapuetic efficacy for treating alcohol abuse and alcohol related conditions. - Identification of factors influencing clinical efficacy of medications 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 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? MECHANISM OF SUPPORT PHASE I Phase I applications in response to this RFA will be funded as Phase I SBIR grants (R43) or STTR grants (R41) with modifications as described below. Responsibility for the planning, direction, and execution of the proposed research will be solely that of the applicant. Applications for Phase I grants should be prepared using the PHS 398 instructions and forms: Please refer to Chapter VI of the PHS 398 instructions prior to preparing an SBIR application. PHS 398 forms specific to SBIR applications are available. See Project Period and Amount of Award The NIAAA intends to commit approximately $1,000,000 in FY 2003 to fund 5 to 10 new grants in response to this RFA. Because the nature and scope of the research proposed may vary, it is anticipated that the size of each award will also vary. Although the financial plans of 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 this RFA will be reissued. Consultant and Contractual Costs The total amount of all consultant costs and contractual costs normally may not exceed 33% of the total costs requested for Phase I SBIR applications. Phase I grant applications submitted under this PA may exceed this limit if the resources required for developing an alcohol sensor and data analysis system are relatively scarce, highly specialized, and multidisciplinary. Deviations must be appropriate and fully justified. Page Limitations The specified page limitations for Phase I applications applies (see SBIR/STTR Omnibus Grant Solicitation at MECHANISM OF SUPPORT - PHASE II Phase II applications in response to this RFA will be awarded as Phase II SBIR grants (R44) or STTR grants. Phase II applications in response to this RFA will only be accepted as competing continuations of previously funded NIH Phase I SBIR awards. The previously funded Phase I award need not have been awarded under this RFA but the Phase II proposal must be a logical extension of the Phase I research. Applications for Phase II awards should be prepared using the PHS 398 instructions and forms: Please refer to Chapter VI of the PHS 398 instructions prior to preparing an SBIR application. PHS 398 forms specific to SBIR applications are available. See Project Period and Amount of Award Phase II applications under this RFA will be considered with a project period up to two years and a budget not to exceed a total cost of $750,000. Any deviations from these limitations must be appropriate and fully justified. Consultant and Contractual Costs The total amount of all consultant costs and contractual costs normally may not exceed 50% of the total costs requested for Phase II SBIR applications. The Fast-Track initiative can be utilized under this RFA. This RFA uses just-in-time concepts. It also uses the modular budgeting format. (see _general_instructions.htm. Specifically, if you are submitting an application budget of $100,000 total costs or less, use the modular format. PROGRAM OBJECTIVES The SBIR program consists of the following three phases: Phase I The objective of Phase I is to establish the technical merit and feasibility of the proposed research, or research and development efforts, and to determine the quality of performance of the small business grantee organization prior to providing further federal support in Phase II. Phase II The objective of this phase is to continue the research or research and development efforts initiated in Phase I. Phase III The objective of this phase, where appropriate, is for the small business concern to pursue the commercialization of the results of the research or research and development funded in Phases I and II. Phase III occurs without SBIR funding. FUNDS AVAILABLE The participating IC(s) intends to commit approximately $1,000,000 in FY 2003 to fund 5 to 10 new SBIR grants in response to this RFA. 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 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 this RFA will be reissued. ELIGIBLE INSTITUTIONS You may submit (an) application(s) if your business has any of the following characteristics: o Independently owned and operated, is not dominant in the field of operation in which it is proposing, has its principal place of business located in the United States, and is organized for profit. o At least 51% owned, or in the case of a publicly owned business, at least 51% of its voting stock is owned by United States citizens or lawfully admitted permanent resident aliens. o Must not have, including its affiliates, more than 500 employees and meets the other regulatory requirements found in 13 CFR Part 121. o Business concerns include, but are not limited to, any individual (sole proprietorship), partnership, corporation, joint venture, association, or cooperative. 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 organization 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. The primary employment of the PI must be with the small business concern at the time of award and during the conduct of the proposed project. Primary employment means that more than one half of the PI's time is spent in the employ of the small business concern. Primary employment with a small business concern precludes full-time employment at another organization. WHERE TO SEND INQUIRIES We encourage your inquiries concerning this PA and welcome the opportunity answer questions from potential applicants. - Direct your questions about scientific/research issues to: Joanne B. Fertig, Ph.D. Division of Clinical and Prevention Research National Institute on Alcohol Abuse and Alcoholism 6000 Executive Boulvard, Suite 505 MSC 7003 Bethesda, MD 20892-7003 For express mail use: Rockville, MD 20852) Telephone: (301) 443-0635 Fax: (301) 443-8774 Email: Mark Egli, Ph.D. Division of Basic Research National Institute on Alcohol Abuse and Alcoholism 6000 Executive Boulevard, Suite 402 Bethesda, MD 20892-7003 [for express mail, use Rockville, MD 20852] Tel. 301-594-6382 FAX 301-594-0673 Email: - Direct your questions about financial or grants management matters to: Judy Fox 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 (301) 443-4704 (telephone) (301) 443-3891 (fax) email: LETTER OF INTENT Prospective applicants are asked to submit a letter of intent by 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: RFA-AA-03-005 Extramural Project Review Branch 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 Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). The PHS 398 is available at in an interactive format. Please refer to Chapter VI of the PHS 398 instructions prior to preparing a SBIR application. PHS 398 forms specific to SBIR applications are available: For further assistance contact GrantsInfo, Telephone (301) 710-0267, Email: Specific Instructions for Modular Grant Applications SBIR applications requesting up to $100,000 per year in total costs (direct costs, indirect costs and fee) 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. Section VI of the research grant application instructions for the PHS 398 (rev. 5/2001) at includes step- by-step guidance for preparing modular grants. Additional information on SBIR modular grants is available at _general_instructions.htm. 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 (MS Word) or (PDF). Sending an Application to the NIH Submit a signed, typewritten original of the application, including the Checklist, and three signed, photocopies, in one package to: Center for Scientific Review National Institutes of Health 6701 Rockledge Drive, Room 1040, MSC 7710 Bethesda, MD 20892-7710 Bethesda, MD 20817 (for express/courier service) At the time of submission, two additional copies of the application must be sent to: Extramural Project Review Branch Office of Scientific Affairs Attn: RFA-AA-03-005 National Institute on Alcohol Abuse and Alcoholism 6000 Executive Blvd., Suite 409 Bethesda, 20892-7003 Telephone: (301) 443-4375 Fax: (301) 443-6077 Application Processing Applications must be received by the application receipt date listed in the heading of this RFA. If an application is received after that date, it will be returned to the applicant without review. The Center for Scientific Review (CSR) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an Introduction addressing the previous critique. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NIAAA. Incomplete and/or non-responsive applications will be returned to the applicant without further consideration. An appropriate peer review group convened by NIAAA in accordance with the review criteria stated below will evaluate applications that are complete and responsive to the RFA for scientific and technical merit. As part of the initial merit review, all applications will: o Receive a written critique o Undergo a selection process in which only those applications deemed to have the highest scientific merit, generally the top half of applications under review, will be discussed and assigned a priority score o Receive a second level review by the appropriate 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 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: - Significance - Approach - Innovation - Investigator - 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, you may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. Review criteria for 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? Review criteria for Phase II applications: - 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 Product Development Plan that adequately addresses the four areas described in the Research Plan item J? - Does the project carry a high degree of commercial potential, as described in the Product Development Plan? Review criteria for Phase I/Phase II Fast Track applications: - 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 Product Development Plan that adequately addresses the four 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 Product Development 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. ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, your application will also be reviewed with respect to the following: o PROTECTIONS: The adequacy of the proposed protection for humans, animals, or the environment, to the extent they may be adversely affected by the project proposed in the application. o INCLUSION: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria included in the section on Federal Citations, below) o DATA SHARING: The adequacy of the proposed plan to share data. o BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Date: December 23, 2002 Application Receipt Date: January 23, 2003 Peer Review Date: March-April 2003 Council Review: June 4, 2003 Earliest Anticipated Start Date: July 1, 2003 AWARD CRITERIA Award criteria that will be used to make award decisions include: Scientific merit (as determined by peer review) Availability of funds Programmatic priorities Commercialization potential Applications will compete for available funds with all other favorably recommended SBIR applications. Note that applicants may achieve all Phase I goals and milestones and still not receive Phase II funding. REQUIRED FEDERAL CITATIONS MONITORING PLAN AND DATA SAFETY AND MONITORING BOARD: Research components involving Phase I and II clinical trials must include provisions for assessment of patient eligibility and status, rigorous data management, quality assurance, and auditing procedures. In addition, it is NIH policy that all clinical trials require data and safety monitoring, with the method and degree of monitoring being commensurate with the risks (NIH Policy for Data Safety and Monitoring, NIH Guide for Grants and Contracts, June 12, 1998: INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: It is the policy of the NIH that women and members of minority groups and their sub- populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the AMENDMENT "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research - Amended, October, 2001," published in the NIH Guide for Grants and Contracts on October 9, 2001 (; a complete copy of the updated Guidelines are available at 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 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 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 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 AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal Domestic Assistance No. 93.273, and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and administered under NIH grants policies described at and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. The PHS strongly encourages all grant recipients to provide a smoke- free workplace and discourage the use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. 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