CLINICAL USE OF MEDICATIONS TO TREAT ALCOHOLISM AND ALCOHOL-RELATED DISEASES RELEASE DATE: April 11, 2002 PA NUMBER: PA-02-098 EXPIRATION DATE: This PA expires on April 15, 2005, unless reissued. National Institute on Alcohol Abuse and Alcoholism (NIAAA) (http://www.niaaa.nih.gov) National Institute on Drug Abuse (NIDA) (http://www.nida.nih.gov) THIS PA CONTAINS THE FOLLOWING INFORMATION o Purpose of this PA o Research Objectives o Mechanism(s) of Support 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 Required Federal Citations PURPOSE The National Institute on Alcohol Abuse and Alcoholism (NIAAA) is seeking research grant applications on the clinical use 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 clinically treat alcohol-induced diseases, such as alcoholic liver diseases, are encouraged as well. In addition, applications can include the utilization of human laboratory paradigms to screen potential medications for subsequent phase 2 and 3 trials as well as to determine the actions of the medications. All applications submitted in response to this program announcement should be conducted in humans. 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); and FG 5974 (and its analogues), a 5-HT1A agonist/5-HT2A antagonist (Roberts et al., 1998). For more than two decades, benzodiazepines have been the most widely used medication for pharmacological management of acute alcohol withdrawal. 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). [The full references for scientific literature cited in this RFA may be obtained from Dr. Joanne Fertig, whose contact information may be found in the section WHERE TO SEND INQUIRIES, below.] 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 for phase 2, 3, and 4 clinical testing and for human laboratory testing 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. - Pharmacological agents need to be identified and their efficacy evaluated in special populations previously understudied in medication trials. Examples of such populations of interest are alcohol abusing/dependent individuals in the criminal justice system, health professions, adolescents, the elderly, and minorities including persons of African heritage and Hispanic/Latino culture, Native Americans/Alaskan Natives, Asian Americans, and Native Hawaiian and Pacific Island Populations. - Development of pharmacological agents to treat alcoholics with comorbid psychopathology such as bipolar disorder, schizophrenia, and anxiety disorders including social phobia and post-traumatic stress disorder. The co-occurrence of psychiatric problems among alcoholics in treatment is frequent. Comorbidity, however, is generally associated with a poorer treatment prognosis as well as high dropout rates and poor compliance. Research needs to include assessment of changes in the comorbid psychopathology as well as changes in drinking outcomes. - 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. - 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? Supported pharmacological investigations should include use of appropriate control groups, adequate sample sizes, and employment of proper statistical analyses. In evaluating the efficacy of all pharmacological agents, it is important to identify subtypes of alcoholics particularly amenable to pharmacological treatment as well as to explore integration of pharmacotherapy with behavioral and verbal therapies. In addition, the experimental treatments should be carefully described, and diagnostic and outcome instruments should reflect state- of-the-art alcoholism assessment. While early clinical studies may employ highly homogeneous samples in a single setting, it is desirable in later-stage research to have greater heterogeneity in samples and sites. Efficacy studies also need to measure compliance with the pharmacological intervention and adequately verify self-reports. Finally, after completion of the active treatment of the clinical trial, it is recommended that subjects be followed-up for at least six months. MECHANISM(S) OF SUPPORT This PA will use the NIH research project grant (R01) small grant (R03) and Exploratory/developmental grant (R21) award mechanism. As an applicant, you will be solely responsible for planning, directing, and executing the proposed project. The total project period for a research project grant (R01) application submitted in response to this Program Announcement may not exceed 5 years. Exploratory/developmental grants (R21) are limited to 3 years for up to $100,000/year for direct costs. (See Program Announcement PA-99-131, "NIAAA Exploratory/Developmental Grant Program," https://grants.nih.gov/grants/guide/pa-files/PA-99- 131.html, for a complete description of the R21 mechanism.) Under the NIAAA Small Grant mechanism (R03) applicants may request either $25,000 or $50,000 in direct costs per year for up to two years. These awards are not renewable; however, a no-cost extension of up to one year may be granted to the grantee institution prior to expiration of the project period. Before completion of the R03, investigators are encouraged to seek continuing support for research through a research project grant (R01). (See Program Announcement PA- 99-098, "NIAAA Small Grant Program," https://grants.nih.gov/grants/guide/pa-files/PAR-99-098.html, for a complete description of the R03 mechanism.) This PA uses just-in-time concepts. It also uses the modular budgeting format. (see https://grants.nih.gov/grants/funding/modular/modular.htm). Specifically, if you are submitting an application with direct costs in each year of $250,000 or less, use the modular format. ELIGIBLE INSTITUTIONS You may submit (an) application(s) if your institution has any of the following characteristics: o For-profit or non-profit organizations o Public or private institutions, such as universities, colleges, hospitals, and laboratories o Units of State and local governments o Eligible agencies of the Federal government o Domestic or foreign o Faith-based organizations 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. WHERE TO SEND INQUIRIES We encourage your inquiries concerning this PA and welcome the opportunity answer questions from potential applicants. o Direct your questions about scientific issues related to alcohol research 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: jfertig@niaaa.nih.gov o Direct your questions about scientific issues related to research involving drug abuse or drug abusing populations to: Jamie Biswas, Ph.D. Chief, Medications Research Grants Branch Division of Treatment Research & Development National Institute on Drug Abuse 6001 Executive Boulevard., Room. 4123, MSC 9551 Bethesda, MD 20892-9551 Telephone: (301) 443-8096 Fax: (301) 443-9649 Email: jb168r@nih.gov o Direct your questions about financial or grants management matters to: Judy Simons Chief, Grants Management Office 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: jsimons@willco.niaaa.nih.gov SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). The PHS 398 is available at https://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 710-0267, Email: GrantsInfo@nih.gov. APPLICATION RECEIPT DATES: Applications submitted in response to this program announcement will be accepted at the standard application deadlines, which are available at https://grants.nih.gov/grants/dates.htm. Application deadlines are also indicated in the PHS 398 application kit. SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: Applications requesting up to $250,000 per year in direct costs must be submitted in a modular grant format. The modular grant format simplifies the preparation of the budget in these applications by limiting the level of budgetary detail. Applicants request direct costs in $25,000 modules. Section C of the research grant application instructions for the PHS 398 (rev. 5/2001) at https://grants.nih.gov/grants/funding/phs398/phs398.html includes step- by-step guidance for preparing modular grants. Additional information on modular grants is available at https://grants.nih.gov/grants/funding/modular/modular.htm. SPECIFIC INSTRUCTIONS FOR APPLICATIONS REQUESTING $500,000 OR MORE PER YEAR: Applications requesting $500,000 or more in direct costs for any year must include a cover letter identifying the NIAAA staff member who has agreed to accept assignment of the application. Applicants requesting more than $500,000 must carry out the following steps: 1) Contact the IC program staff at least 6 weeks before submitting the application, i.e., as you are developing plans for the study; 2) Obtain agreement from the IC staff that the IC will accept your application for consideration for award; and, 3) Identify, in a cover letter sent with the application, the staff member and IC who agreed to accept assignment of the application. This policy applies to all investigator-initiated new (type 1), competing continuation (type 2), competing supplement, or any amended or revised version of these grant application types. Additional information on this policy is available in the NIH Guide for Grants and Contracts, October 19, 2001 at https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-004.html. 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) APPLICATION PROCESSING: Applications must be received by or mailed before the receipt dates described at https://grants.nih.gov/grants/funding/submissionschedule.htm. The 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. 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 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: o Significance o Approach o Innovation o Investigator o Environment The scientific review group will address and consider each of these criteria in assigning your application's overall score, weighting them as appropriate for each application. Your application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, you may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. (1) SIGNIFICANCE: Does your study address an important problem? If the aims of your application are achieved, how do they advance scientific knowledge? What will be the effect of these studies on the concepts or methods that drive this field? (2) APPROACH: Are the conceptual framework, design, methods, and analyses adequately developed, well integrated, and appropriate to the aims of the project? Do you acknowledge potential problem areas and consider alternative tactics? (3) INNOVATION: Does your project employ novel concepts, approaches or methods? Are the aims original and innovative? Does your project challenge existing paradigms or develop new methodologies or technologies? (4) INVESTIGATOR: Are you appropriately trained and well suited to carry out this work? Is the work proposed appropriate to your experience level as the principal investigator and to that of other researchers (if any)? (5) ENVIRONMENT: Does the scientific environment in which your work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, your application will also be reviewed with respect to the following: PROTECTIONS: The adequacy of the proposed protection for humans or the environment, to the extent they may be adversely affected by the project proposed in the application. 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) BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. OTHER REVIEW CRITERIA: AWARD CRITERIA Applications submitted in response to a PA will compete for available funds with all other recommended 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 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: https://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 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 (https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines are available at https://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2 001.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 https://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 https://grants.nih.gov/grants/guide/notice- files/NOT-OD-00-039.html. 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 https://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 a 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 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 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 https://grants.nih.gov/grants/policy/policy.htm 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. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people. https://grants.nih.gov/grants/guide/pa-files/PA-02-015.html.
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