COMPETING CONTINUATION AWARDS OF SBIR/STTR PHASE II GRANTS FOR PHARMACOLOGICAL AGENTS AND BIOMARKERS FOR ALCOHOLISM AND ALCOHOL-RELATED DISEASES RELEASE DATE: May 29, 2003 PA NUMBER: PA-03-129 EXPIRATION DATE: This PA will expire on May 30, 2006, unless re-issued. IMPORTANT CHANGE: The opportunity to apply for an NIAAA SBIR and STTR Phase II Competing Renewal is available from the PHS 2006-2 SBIR/STTR Omnibus Solicitation. (See Program Descriptions and Research Topics (PDF or MS Word)). Interested applicants must apply using the electronic application package from the parent SBIR (PA-06-120) or STTR (PA-06-121) Funding Opportunity Announcements (FOAs). APPLICATIONS MAY NOT BE SUBMITTED IN PAPER FORMAT. National Institute on Alcohol Abuse and Alcoholism (NIAAA) (http://www.niaaa.nih.gov) CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER: 93.273 APPLICATION RECEIPT DATE(S): NOTICE: This program announcement (PA) 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) contains information about the SBIR and STTR programs, regulations governing the programs, and instructional information for submission. All of the instructions within the current SBIR/STTR Omnibus Solicitation apply. THIS PA CONTAINS THE FOLLOWING INFORMATION: o Purpose of the PA o Research Objectives o Mechanism(s) of Support o Project Period and Amount of Award o Eligibility o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Where to Send Inquiries o Submitting an Application o Peer Review Process o Review Criteria o Award Criteria o Receipt and Review Schedule o Required Federal Citations PURPOSE OF THE PA The SBIR/STTR programs were initiated as a means for government agencies to use small businesses to stimulate technological innovation and to help agencies meet their research and development (R&D) needs. An additional provision of these programs is the expected commercialization of the research. Certain types of research require clinical evaluation and Federal regulatory approvals before the Phase III of the small business research pathway can ever be realized. A recipient of an NIH SBIR/STTR Phase I and Phase II award normally receives no more than $1 million. If the intended commercialized product is a medical device, drug, or biologic, the $1 million often represents a small fraction of the funds necessary to complete the studies required for approval and licensing by the Food and Drug Administration (FDA) or other Federal agencies. Moreover, a recipient of an NIH SBIR/STTR Phase I and Phase II award normally receives less than three years of support. Yet, the process of moving promising new products from bench to bedside typically takes more than a decade. The drug discovery timeline, for example, starts with identification of an agent or class of agents with particular activity, identification and optimization of lead compounds, and subsequent pre-clinical testing of these compounds for safety and toxicity. Those agents still considered viable after such rigorous scrutiny are then brought to human subjects for clinical evaluation of a variety of aspects of the agent, including safety, efficacy, and dosage determination. Similarly long timelines obtain for other products intended to understand, diagnose, prevent, or treat human health disorders (e.g., medical devices, vaccines). Despite the cost and the length of time required to move such products from the laboratory to the patient, these are precisely the products with potential to contribute significantly to the economy of the nation and to the health of her people. The intent of the SBIR/STTR Phase II competing continuation grants is to support such research and development. The purpose of this Program Announcement (PA) is to solicit from Phase II SBIR/STTR awardees grant applications that propose to continue the process of developing products that ultimately require: 1) clinical evaluation and 2) approval of a Federal regulatory agency. Such products include, but are not limited to: drugs, vaccines, alcohol-sensitive biochemical markers, radioligands, medical implants, imaging protocols proposed for clinical use, and medical devices. RESEARCH OBJECTIVES Background During the past decade advances have been made in medications development to treat alcoholism. 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. Acamprosate has also been studied extensively in Europe and is currently approved for alcoholism treatment in over 24 countries. Ondansetron and gabapentin are two more promising medications that are currently being evaluated in clinical trials. 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. This recent knowledge has led to many biological targets for testing novel pharmacological agents. Because medications mentioned above produce small to medium effects to reduce or prevent drinking, development and evaluation of 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; kudzu and its purified active components (e.g., puerarin); corticotropin-releasing factor (CRF) antagonists; opioid receptor subtype antagonists such as delta2 antagonist naltriben; 6-beta naltrexol, an active metabolite of naltrexone; synthetic neurosteroids; 1-aminocyclopropanecarboxylic acid (ACPC), a NMDA partial agonist; FG 5974 (and its analogues), a 5-HT1A agonist/5-HT2A antagonist; and agents with selective affinity to GABAA alpha1 or GABAA alpha5 receptor subunits. 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. Progress has also been made in elucidating the mechanisms of alcohol-induced organ damage. In particular, several primary factors underlying the pathogenesis of alcoholic liver disease have been identified including cytokines and reactive oxygen species (ROS). For example, antioxidants, such as S-adenosyl-L- methionine (SAMe), have 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 anti-fibrotic agent; and metformin, an insulin-sensitizing agent. The development of effective biochemical markers represents a powerful means for early diagnosis and treatment of alcohol dependent/abuse patients and for the identification of individuals who have a predisposition for alcoholism. There are two different types of alcohol-sensitive biochemical markers: trait markers and state markers. Trait biomarkers have the ability to detect inborn characteristics of individuals who are vulnerable for alcoholism. This type of marker would be invaluable for screening of high-risk individuals (e.g., children of alcoholics) and targeting them with preventive or early treatment interventions. In addition, trait markers might assist practitioners in identifying subpopulations of alcoholics who may need different treatment strategies. An ideal trait marker should have several features. First, it should display validity in detecting people susceptible to alcoholism, particularly before the onset of alcoholism or during periods of stable abstinence. Second, it should be measured easily and reliably. Third, it should be specific for only alcoholism and not affected by other medical or psychiatric disorders or drugs. Since alcoholism is a complex disease, it is likely that more than one type of gene and protein exist as a trait marker. State markers or markers of alcohol consumption serve several important purposes. First, they can assist physicians in diagnosing individuals with chronic drinking problems, particularly patients who deny excessive drinking. Moreover, they may also identify individuals in early stages of heavy drinking, thus avoiding the long-term medical, psychological, and social consequences of chronic alcoholism. Second, state biomarkers can aid in the diagnosis and treatment of other diseases (liver diseases, pancreatitis, and cardiovascular diseases) that were, at least, caused by excessive drinking. Biomarkers that detect alcohol-induced tissue/organ damage would be particularly valuable. Third, they are useful in alcohol treatment and prevention programs. Since the goal of many programs is abstinence, monitoring relapse is important in gauging success. Last, state biomarkers are important in clinical alcohol trials. Although measurement of self- report has become more sophisticated (e.g., Timeline Followback), it still relies on accurate reporting. These biomarkers would be essential in at least confirming the self-report. There are several ideal features of a state marker. These include high validity, reliability, stability, reasonable cost, practicability, acceptability to both practitioners and patients, and transportability in different settings. Several biomarkers are currently being used including carbohydrate-deficient transferrin (CDT), gamma glutamy transferase (GGT), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and mean corpuscular volume (MCV). Many of these markers are elevated due to alcohol- induced tissue damage. Unfortunately, these markers have limitations, and thus new markers need to be developed. Example of Research Topics These examples are meant for illustrative purposes and are not exclusive of other appropriate activities: o Preclinical studies, including pharmacology and toxicology, beyond those conducted under the Phase I (R43) and initial Phase II (R44) grants. Some in vivo or in vitro studies would be expected to have been carried out in Phase I or the initial Phase II grant. o Completion of studies as required by the Food and Drug Administration (FDA) for Investigational New Drug (IND) or Radioactive Drug Research Committee (RDRC) application. o Development and clinically evaluation of new alcohol-sensitive biomarkers o Assessment of devices with regard to performance standards related to the FDA approval process. o Safety and effectiveness studies of novel medical devices. o Biocompatibility studies of surface materials of putative medical implants. o Evaluation of novel imaging approaches for diagnostic purposes. o Clinical studies in support of New Drug Application approval by the FDA. o Clinical studies in support of Pre-Market Approval for biomarkers/medical devices by the FDA. MECHANISM(S) OF SUPPORT Unsolicited SBIR/STTR competing continuation applications will not be accepted. That is, an SBIR/STTR Phase II competing continuation application must be in response to this PA, and the application will only be accepted as a competing continuation of a previously funded NIH Phase II SBIR or STTR award (R44 mechanism, R42 mechanism.) The previously funded NIH Phase II grant need not have been submitted in response to any particular solicitation, but the application for the competing continuation must propose research and development that represents a logical extension of the previously supported Phase II research as described in the announcement. The applicant will be solely responsible for planning, directing, and executing the proposed project. The SBIR/STTR Phase II competing continuation would represent a continuation of support for research/research and development of such previous work funded by the original Phase II R44 grant. The expectation is that as a result of support from a previous SBIR/STTR Phase I (R43) and Phase II (R44) grant, promising results had been produced that indicate not only the merit of further research and development, but also that clinical investigations and Federal regulatory approvals will ultimately be required to realize the potential of the product being researched and developed. Activities supported by a competing continuation of a Phase II SBIR/STTR grant may include an extension and expansion of preclinical research and development, clinical testing, and other scientific research and development activities that would ultimately be useful in meeting the requirements and expectations of Federal regulatory processes. A competing continuation Phase II award should not, however, be used to conduct very early stage research (e.g., identifying targets for drugs, initial identification of lead compounds, etc.). In addition, like a Phase I and initial Phase II grant, the competing continuation Phase II award will not support costs for legal consultation, marketing efforts, etc. PROJECT PERIOD AND AMOUNT OF AWARD Awards routinely will be in the range of $750,000 to $1,000,000 total costs per year for up to three years. Because the length of time and cost of drug discovery and development represents a long term research and development commitment, a project period of up to three years and a budget not to exceed total costs of $1,000,000 per year (including direct costs, indirect costs and fee/profit) will be considered under this PA if the time period and amount are well 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 initial SBIR Phase II applications. SBIR Phase II competing continuation grant applications submitted under this PA may exceed this guideline, however, when well justified and when those costs are necessary to support clinical studies or trials and related expenses. Examples of well founded reasons for exceeding this guideline include, but are not limited to, subcontracts to clinical research organizations to carry out aspects of clinical evaluation or subcontracts to assure compliance with Good Manufacturing Practices (GMPs) expectations of the FDA. For STTR Phase II applications, the small business MUST perform at least 30% of the research/R&D and the partnering research institution must perform at least 40% of the proposed research/R&D. Commercialization Plan All Phase II grant applications, including this competing continuation application, require a "Commercialization Plan [formerly "Product Development Plan,"] as described in Item j of the SBIR/STTR Phase II instructions (PDF or MS Word). The Commercialization Plan is meant in part to demonstrate the commercial viability of the product researched and developed with SBIR support. Since this Phase II competing continuation application mechanism supports a more advanced stage of research and development than the R44 Phase II mechanism, the Commercialization Plan should reflect more advanced plans and arrangements for commercialization than what might be submitted for an R44 application. For example, part of a Commercialization Plan that would be appropriate to drug development supported by a Competing Continuation application would be a clear indication of an arrangement (e.g., strategic alliance, letters of support) with another party through which the final stages of the work might be supported or carried out, including additional clinical trials, FDA submissions, drug manufacturing and drug commercialization. This example is meant for illustrative purposes; the details of any Commercialization Plan will depend upon the particular circumstances represented in a given application. ELIGIBILITY Eligible to apply for SBIR/STTR Phase II competing continuation awards are NIH SBIR/STTR Phase II awardees that meet the definition of a small business concern (as described in the NIH SBIR/STTR Phase II instructions) and whose projects are developing products that would ultimately require clinical studies and Federal regulatory approval. The previously funded Phase II SBIR/STTR grant need not have been submitted in response to a particular solicitation, as long as the research is appropriate to the purpose of this PA. ELIGIBLE INSTITUTIONS The competing continuation application must be a continuation of a previously completed Phase II (R44) SBIR/ Phase II STTR (R42) grant focusing on research and development of a product or products ultimately requiring clinical testing and Federal regulatory approval. To maintain eligibility to seek a Phase II competing continuation grant, a Phase II grantee organization should submit an application for the Phase II competing continuation grant within the first six receipt dates following the expiration of the initial Phase II budget. Other eligibility requirements for a Phase II competing continuation grant are identical to those for the initial Phase II (R44) applications and can be found at http://grants.nih.gov/grants/funding/sbirsttr2/PhaseII_SBIRSTTR.pdf (PDF) or http://grants.nih.gov/grants/funding/sbirsttr2/PhaseII_SBIRSTTR.doc (MS Word) 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. WHERE TO SEND INQUIRIES We encourage your inquiries concerning this PA and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into two areas: scientific/research and financial or grants management issues: o 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 Boulevard, Suite 505 MSC 7003 Bethesda, MD 20892-7003 (for courier, use Rockville, MD 20852) Telephone: (301) 443-0635 Fax: (301) 443-8774 Email: jfertig@niaaa.nih.gov Peter B. Silverman, Ph.D. Division of Basic Research National Institute on Alcohol Abuse and Alcoholism 6000 Executive Boulevard, Suite 402 Bethesda, MD 20892-7003 (for courier, use Rockville, MD 20852) Tel. 301-402-6966 FAX 301-594-0673 Email: psilverm@mail.nih.gov o Direct your questions about financial or grants management matters to: Judy Fox (formerly Simons) Grants Management Branch National Institute on Alcohol Abuse and Alcoholism 6000 Executive Boulevard, Suite 505 MSC 7003 Bethesda, MD 20892-7003 (for courier, use Rockville, MD 20852) Telephone: (301) 443-2434 Email: jsimons@niaaa.nih.gov SUBMITTING AN APPLICATION The PHS 398 research grant application must be used for all SBIR/STTR Phase I, Phase II and Fast-Track applications (new and revised.) The PHS 398 is available at http://grants.nih.gov/grants/funding/phs398/phs398.html. Prepare your application in accordance with the SBIR/STTR Omnibus Solicitation and the PHS 398. Helpful information on the preparation of the application can be obtained at: http://grants.nih.gov/grants/funding/sbirgrantsmanship.pdf. The NIH will return applications that are not submitted using the PHS 398 grant application. For further assistance contact GrantsInfo, Telephone (301) 710-0267, Email: GrantsInfo@nih.gov. All Phase II SBIR/STTR grant applications, including this competing continuation application, require a "Commercialization Plan," as described in item J of the Phase II SBIR Instructions http://grants.nih.gov/grants/funding/sbir.htm). The Commercialization Plan is meant, in part, to demonstrate the commercial viability of the product researched and developed with SBIR support. Since this Phase II competing continuation application mechanism supports a more advanced stage of research and development than the R44 Phase II mechanism, the Commercialization Plan should reflect more advanced plans and arrangements for commercialization than what might be submitted for an initial R44 application. For purposes of identification and processing, enter the following title and number of this PA in item 2 on the face page of the application: PA-03-129; "COMPETING CONTINUATION PHASE II SBIR/STTR NIAAA" APPLICATION RECEIPT DATES: Applications submitted in response to this program announcement will be accepted at the standard application deadlines, which are available at http://grants.nih.gov/grants/dates.htm. Application deadlines are also indicated in the PHS 398 application kit. SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of the application, including the checklist, and five 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) Applications must be received by or mailed on or before the receipt dates described on the first page of this program announcement. The Center for Scientific Research (CSR) will not accept any application in response to this PA 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 a substantial revision of an application already reviewed, but such application must include an Introduction addressing the previous critique. 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. PEER REVIEW PROCESS Applications submitted for this PA will be assigned on the basis of established PHS referral guidelines. An appropriate scientific review group convened in accordance with the standard NIH peer review procedures (http://www.csr.nih.gov/refrev.htm) will evaluate applications for scientific and technical merit. 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 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 the 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 ALL SBIR/STTR APPLICATIONS 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? 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? Innovation: Does the project challenge existing paradigms or employ novel technologies, approaches or methodologies? Are the aims original and innovative? 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? Environment: Is there sufficient access to resources (e.g., equipment, facilities)? Does the scientific and technological environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the following items will be applied to ALL 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? 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.) Protection of Human Subjects from Research Risks - for all studies involving human subjects. See instructions and "Guidance for Preparing the Human Subjects Research Section." o 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? o 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? o Are the plans proposed for the protection of human subjects adequate? 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.) o 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? o 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? o 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? 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. o 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? ADDITIONAL CONSIDERATIONS: The following items may be also be considered by reviewers but will not be included in the determination of scientific merit. 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. 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? AWARD CRITERIA Applications submitted in response to a PA 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 RECEIPT AND REVIEW SCHEDULE See http://grants.nih.gov/grants/funding/sbirsttr_receipt_dates.htm 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 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. 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. 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 PA 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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