PAR-00-095: ANCILLARY STUDIES TO NIMH MULTI-SITE CLINICAL TRIALS

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ANCILLARY STUDIES TO NIMH MULTI-SITE CLINICAL TRIALS Release Date: May 17, 2000 (see addenda NOT-MH-01-005, NOT-MH-00-009, NOT-MH-00-012) PA NUMBER: PAR-00-095 National Institute of Mental Health THIS PA USES "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. THIS PA INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED WHEN PREPARING AN APPLICATION IN RESPONSE TO THIS PA. PURPOSE The National Institute of Mental Health (NIMH) recently issued four contracts to support multi-site clinical trials in schizophrenia, Alzheimer’s disease, bipolar disorder, treatment resistant depression, and adolescent depression. Information about these trials is available on the NIMH website at http://www.nimh.nih.gov/studies/index.cfm. NIMH invites investigator- initiated research project applications for ancillary studies that extend the utility of the national resource created in these trials. The purpose of ancillary studies is to promote innovative lines of scientific inquiry regarding the understanding and treatment of mental disorders. Ancillary studies may use subjects recruited in a trial; may be an expansion into a new (related) population at some or all of the clinical sites participating in the trial; or may simply share methods and measures with the trial. Ancillary studies must not interfere with the objectives of a trial, and each trial has an Ancillary Study Committee to review the appropriateness of proposed projects. The website for each trial contains ancillary study policies and procedures. Current participation in a trial as a principal investigator, co-investigator, consultant, or clinical site investigator is not a prerequisite for submission of an ancillary study application. 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 Program Announcement (PA), Ancillary Studies to NIMH Multi-Site Clinical Trials, is related to the priority areas of Mental Health and Mental Disorders. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople/ ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign, for-profit and non- profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal government. Foreign institutions are not eligible for the Small Grant (R03) mechanism. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as principal investigators. MECHANISM OF SUPPORT This PA will use the following research grant mechanisms: Small Grants (R03), Exploratory/Developmental Grants (R21), Research Project Grants (R01), and Collaborative R01s for Clinical Studies of Mental Disorders. The Small Grant (R03) provides two years of funding with a maximum of $50,000 direct costs for each year. The Exploratory/Developmental Grant (R21) provides up to three years of funding with up to $125,000 in total direct costs annually, and is intended for pilot testing of interventions and other aspects of intervention development. The Research Project Grant (R01) provides up to five years of funding that is commensurate with the science proposed. Collaborative R01s for Clinical Studies of Mental Disorders (CSMD) support research that requires multiple sites and Principal Investigators. For all competing R03 and R21 applications, and R01 applications requesting up to $250,000 direct costs per year, specific application instructions have been modified to reflect "MODULAR GRANT" and "JUST-IN-TIME" streamlining efforts being undertaken at NIH. More detailed information about modular grant applications, including a sample budget narrative justification pages and a sample biographical sketch, is available via the Internet at: http://grants.nih.gov/grants/funding/modular/modular.htm. R01 applications that request more than $250,000 in any year must use the standard PHS 398 (rev. 4/98) application instructions. Small Grants (RO3s), Exploratory/Developmental Grants (R21), and Collaborative R01s for Clinical Studies of Mental Disorders, have special eligibility requirements, application formats, and review criteria. Applicants are strongly encouraged to consult with program staff (listed under INQUIRIES) and to obtain the appropriate additional announcements for those grant mechanisms. These can be found at: http://grants.nih.gov/grants/guide/pa-files/PAR-99-140.html (R03); http://grants.nih.gov/grants/guide/pa-files/PA-99-134.html (R21); http://grants.nih.gov/grants/guide/pa-files/PAR-98-017.html (Collaborative R01s). RESEARCH OBJECTIVES BACKGROUND The National Institute of Mental Health (NIMH) has made a major commitment to support treatment research that directly affects and improves public health. This effectiveness model is a relatively new approach for mental health treatment researchers, whose studies in the past have either been clinical trials focused on short term efficacy and regulatory issues, or studies of systems of care and service utilization. NIMH has issued contracts for four large-scale multi-site clinical trials: (1) Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) to investigate strategies for managing bipolar disorder, (2) Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) to study the effectiveness of the new atypical antipsychotics in schizophrenia and Alzheimer’s disease, (3) Sequenced Treatment Alternatives to Relieve Depression (STAR*D) to develop algorithms for managing resistant depression, and (4) Treatment of Adolescents with Depression Study (TADS). Information about the objectives of each of these trials, detailed study protocols, and participating investigators and sites can be found at http://www.nimh.nih.gov/studies/index.cfm. The trials supported by these contracts address fundamental questions about the day-to-day care of people with mental illness. However, despite their size and the level of NIMH’s commitment, they will not be able to answer all relevant issues. They are only a beginning, and one of NIMH’s goals in funding these contracts is to develop an infrastructure to facilitate and foster investigator-initiated research grants that focus on understanding the nature and course of illness and on improving treatment in the community. This Program Announcement invites research project applications that make use of the infrastructures developed in the NIMH clinical trial contracts. The scope of these projects could range from small pilot studies to multi-site, multi-principal investigator collaborative research projects. NIMH is particularly interested in fostering projects by new investigators, as well as translational research studies that apply basic science findings in a clinical setting. Ancillary studies might use subjects recruited in the trials, or might be an expansion into a new (related) population at the clinical sites participating in the trial, or might simply share data, methods and resources with the trials. The distinguishing feature of an ancillary study is that it either requires the resources of a trial to achieve its goals, or that this involvement and interaction with a trial significantly enhances the ancillary study’s efficiency or scientific value. Current participation in a trial as a principal investigator, co- investigator, consultant, or clinical site investigator is not a prerequisite for submission of an ancillary study application (although these investigators can also propose ancillary studies). Since ancillary studies may involve close interaction with trial participants or personnel, it is important that the projects be coordinated. In particular, ancillary studies must not interfere with the objectives of the trial, and an ancillary study must be approved by the trial before NIMH will consider funding an application. Each trial has established an Ancillary Study Committee (ASC) to review proposed projects for appropriateness prior to submitting an application to NIMH or other potential funding sources. The ASC will also serve as a point of initial contact for investigators interested in an ancillary study, and will help formulate methods and develop budgets. Each Trial ASC has established its own policies and procedures, which can be obtained via http://www.nimh.nih.gov/studies/index.cfm. There are currently four multi-site NIMH clinical trials for which ancillary studies may be considered: (1) Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD): The overall goal of this project is to improve treatment of bipolar disorder by identifying optimal treatments for normalizing mood and preventing recurrence, as well as providing answers to a host of important questions confronting clinicians who treat bipolar disorder. The primary objectives are 1) developing a registry of bipolar patients treated in diverse settings by a network of clinicians following common clinical practice guidelines; 2) determining the most effective strategies for treatment of the depressed phase of bipolar illness; and 3) determining which maintenance strategies most effectively prevent recurrence of affective episodes. (2) Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE): The projects includes two separate trials with a common administrative and operational core, studying the new atypical antipsychotics in people with schizophrenia and people with Alzheimer’s disease. The primary objectives of the schizophrenia trial are to determine the cost effectiveness of the new atypical antipsychotics compared to conventional agents and to determine the differential effectiveness of the new atypical antipsychotics compared to one another. The primary objective of the Alzheimer’s disease trial is to study the effectiveness of the new atypical antipsychotics in managing psychosis and severe agitation in people with Alzheimer’s disease. (3) Sequenced Treatment Alternatives to Relieve Depression (STAR*D): The overall goal of this project is to develop and evaluate clinical strategies for improving outcomes for outpatients with treatment resistant depression in both primary care and specialty settings. The primary objectives are (a) to determine which "next step" treatments are acceptable to depressed patients who have failed previous treatments, and provide maximal clinical benefit with minimal side effects; (b) studying how well these next step treatments prevent subsequent relapses; and (c) providing estimates of the relative costs effectiveness and benefits of these treatments. (4) Treatment of Adolescents with Depression Study (TADS): This project compares the effectiveness of different treatment modalities in 12-17 year old patients with major depressive disorder. In this multi-site trial, a total of 432 teens will be randomized to either pharmacotherapy with fluoxetine, cognitive-behavioral therapy, combined cognitive-behavioral therapy plus fluoxetine, or clinical management with placebo medication. Treatment continues for up to 9 months, depending on clinical response, with a post-treatment follow-up of 12 months. EXAMPLES Examples of appropriate ancillary studies include (but are not limited to) the following (please note that NIMH’s interest in these topics does not guarantee approval by a trial’s ASC): o Developing and testing specific treatment interventions for patients who are screened for a trial but do not meet the entry criteria, or who reach a study end-point. o Studying treatment effects on additional outcome variables not included in the initial trial protocol. o Investigating potential moderators and mediators of treatment effects (including side effects) not already included in the trial protocol o Follow-up assessments of patients who have completed a trial. o Population pharmacokinetics of drugs used in a trial. o Development of pharmacogenetic databases using samples and data from trial subjects. o Coordination with existing or new brain banks by characterizing patients ante-mortem, securing patient and family permission, and collecting post- mortem brain tissue. o Investigations with neuroimaging measures of brain function (PET, SPECT, MRI, MRS) to identify, characterize, and validate biomarkers that predict treatment response, non-response, or placebo response. o Investigations with neuroimaging measures of brain function (PET, SPECT, MRI, MRS) to identify the sites and therapeutic mechanisms of action of different psychotropic drugs. o Investigation of illness state, treatment, service use, and outcomes in persons excluded from a trial because of risk of suicide. o Development of interventions to manage suicidality in persons excluded from a trial due to risk for suicide. o Determining patient, provider and encounter factors that may enhance or detract from the effective delivery of interventions. o Assessing and testing methods to more quickly and effectively synthesize and incorporate results from a trial into clinical practice. o Characterizing system and organizational factors/processes that interfere with clinical care of subjects in a trial. o Investigating and optimizing procedures for assessing capacity and obtaining informed consent in trial participants. o Examining stigma and its effects in trial subjects. o Examining ethnicity, cultural, and socioeconomic factors that influence outcome in trial participants, including their effects on help-seeking behavior, formation of therapeutic alliances, and adherence to treatment. o Investigations of basic behavioral processes (e.g., cognition, emotion, motivation, personality, social cognition) to identify how these processes are altered in disorder and/or predict treatment response, non-response, or placebo response. o Investigations of the effects of atypical antipsychotics on metabolism and endocrine function. o Investigations of the effects of the new atypical antipsychotics on cardiovascular physiology. o Investigations of the effects of sex hormones on antidepressant treatment response in patients demonstrating treatment resistant depression. o Development and refinement of psychosocial interventions to enhance adherence to antidepressant medication or psychotherapy regimens in patients demonstrating treatment resistant depression. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their subpopulations must be included in all NIH supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification is provided 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 research involving human subjects should read the "NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical Research," which have been published in the Federal Register of March 28, 1994 (FR 59 14508-14513) and in the NIH Guide for Grants and Contracts, Vol. 23, No. 11, March 18, 1994 available on the web at the following URL address: http://grants.nih.gov/grants/guide/notice-files/not94-100.html INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of NIH 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 was published in the NIH Guide for Grants and Contracts, March 6, 1998, and is available at the following URL address: http://grants.nih.gov/grants/guide/notice-files/not98-024.html Investigators also may obtain copies of these policies from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. 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. Reviewers are cautioned that their anonymity may be compromised when they directly access an Internet site. APPLICATION PROCEDURES An ancillary study application must provide written proof of approval from a trial’s Principal Investigator and its Ancillary Study Committee (ASC) or Executive Committee both before NIMH accepts it for scientific review, and again before an award is made. Applicants are strongly encouraged to contact the program contacts listed under INQUIRIES with any questions regarding their proposed project and the goals of this PA and other programmatic priorities. Applications are to be submitted on the grant application form PHS 398 (rev. 4/98) and will be accepted at the standard application deadlines as indicated in the application kit. Application kits are available at most institutional offices of sponsored research and from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone (301) 435-0714, Email: GrantsInfo@nih.gov. Applications are also available on the World Wide Web at: http://grants.nih.gov/grants/forms.htm. For all competing R03, R21 and R01 applications requesting up to $250,000 direct costs per year, specific application instructions have been modified to reflect "MODULAR GRANT" and "JUST-IN-TIME" streamlining efforts being undertaken at NIH. Applications that request more than $250,000 in any year must use the standard PHS 398 (rev. 4/98) application instructions. SPECIFIC APPLICATION INSTRUCTIONS FOR MODULAR GRANTS The modular grant concept establishes specific modules in which direct costs may be requested as well as a maximum level for requested budgets. Only limited budgetary information is required under this approach. The just-in-time concept allows applicants to submit certain information only when there is a possibility for an award. It is anticipated that these changes will reduce the administrative burden for the applicants, reviewers and Institute staff. The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants, with the modifications noted below. BUDGET INSTRUCTIONS Modular Grant applications will request direct costs in $25,000 modules, up to a total direct cost request of $250,000 per year. (Applications that request more than $250,000 direct costs in any year must follow the traditional PHS 398 application instructions.) The total direct costs must be requested in accordance with the program guidelines and the modifications made to the standard PHS 398 application instructions described below: PHS 398 o FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in $25,000 increments up to a maximum of $250,000) and Total Costs [Modular Total Direct plus Facilities and Administrative (F&A) costs] for the initial budget period. Items 8a and 8b should be completed indicating the Direct and Total Costs for the entire proposed period of support. o DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD - Do not complete Form Page 4 of the PHS 398. It is not required and will not be accepted with the application. o BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT - Do not complete the categorical budget table on Form Page 5 of the PHS 398. It is not required and will not be accepted with the application. o NARRATIVE BUDGET JUSTIFICATION - Prepare a Modular Grant Budget Narrative page. (See http://grants.nih.gov/grants/funding/modular/modular.htm for sample pages.) At the top of the page, enter the total direct costs requested for each year. This is not a Form page. o Under Personnel, list key project personnel, including their names, percent of effort, and roles on the project. No individual salary information should be provided. However, the applicant should use the NIH appropriation language salary cap and the NIH policy for graduate student compensation in developing the budget request. For Consortium/Contractual costs, provide an estimate of total costs (direct plus facilities and administrative) for each year, each rounded to the nearest $1,000. List the individuals/organizations with whom consortium or contractual arrangements have been made, the percent effort of key personnel, and the role on the project. Indicate whether the collaborating institution is foreign or domestic. The total cost for a consortium/contractual arrangement is included in the overall requested modular direct cost amount. Include the Letter of Intent to establish a consortium. Provide an additional narrative budget justification for any variation in the number of modules requested. o BIOGRAPHICAL SKETCH - The Biographical Sketch provides information used by reviewers in the assessment of each individual's qualifications for a specific role in the proposed project, as well as to evaluate the overall qualifications of the research team. A biographical sketch is required for all key personnel, following the instructions below. No more than three pages may be used for each person. A sample biographical sketch may be viewed at: http://grants.nih.gov/grants/funding/modular/modular.htm - Complete the educational block at the top of the form page; - List position(s) and any honors; - Provide information, including overall goals and responsibilities, on research projects ongoing or completed during the last three years. - List selected peer-reviewed publications, with full citations; o CHECKLIST - This page should be completed and submitted with the application. If the F&A rate agreement has been established, indicate the type of agreement and the date. All appropriate exclusions must be applied in the calculation of the F&A costs for the initial budget period and all future budget years. o The applicant should provide the name and phone number of the individual to contact concerning fiscal and administrative issues if additional information is necessary following the initial review. Applicants planning to submit an investigator-initiated new (type 1), competing continuation (type 2), competing supplement, or any amended/revised version of the preceding grant application types requesting $500,000 or more in direct costs for any year are advised that he or she must contact Institute program staff before submitting the application, i.e., as plans for the study are being developed. Furthermore, the application must obtain agreement from Institute staff that the Institute will accept the application for consideration for award. Finally, the applicant must identify, in a cover letter sent with the application, the staff member and Institute who agreed to accept assignment of the application. This policy requires an applicant to obtain agreement for acceptance of both any such application and any such subsequent amendment. Refer to the NIH Guide for Grants and Contracts, March 20, 1998 at http://grants.nih.gov/grants/guide/notice-files/not98-030.html Any application subject to this policy that does not contain the required information in a cover letter sent with the application will be returned to the applicant without review. The title and number of the program announcement must be typed on line 2 of the face page of the application form and the YES box must be marked. 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: Henry Haigler, Ph.D. National Institute of Mental Health 6001 Executive Boulevard, Room 6154, MSC 9609 Bethesda, MD 20892-9609 REVIEW CONSIDERATIONS Applications will be assigned on the basis of established PHS referral guidelines. Applications will be evaluated for scientific and technical merit by an appropriate scientific review group convened by NIMH. As part of the initial merit review, all applications will receive a written critique and undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of applications under review, will be discussed, assigned a priority score, and 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. Each of these criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application. Note that the application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. (1) Significance: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? (2) Approach: Are the conceptual framework, design, methods, and analyses adequately developed, well-integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? (3) Innovation: Does the project employ novel concepts, approaches or methods? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? (4) Investigator: Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? (5) Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? In addition to the above criteria, in accordance with NIH policy, all applications will also be reviewed with respect to the following: o The adequacy of plans to include both genders, minorities and their subgroups, and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. o The reasonableness of the proposed budget and duration in relation to the proposed research o 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. AWARD CRITERIA Applications will compete for available funds with all other recommended applications assigned to the Institute. The following will be considered in making funding decisions: Quality of the proposed project as determined by peer review, availability of funds, and program priority. INQUIRIES Inquiries are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding issues related to the trials as well as scientific issues related to programs in the Division of Services and Interventions Research to: John K. Hsiao, M.D. Division of Services and Intervention Research National Institute of Mental Health 6001 Executive Boulevard, Room 7160, MSC 9635 Bethesda, MD 20892-9635 Telephone: (301) 443-1185 FAX: (301) 594-6784 Email: jhsiao@helix.nih.gov Direct inquiries regarding scientific issues related to programs in the Division of Mental Disorders, Behavior, and AIDS to: Bruce Cuthbert, Ph.D. Division of Mental Disorders, Behavior, and AIDS National Institute of Mental Health 6001 Executive Boulevard, Room 6184, MSC 9625 Bethesda, MD 20892-9651 Telephone: (301) 443-3728 FAX: (301) 443-4611 Email: bcuthbert@mail.nih.gov Direct inquiries regarding scientific issues related to programs in the Division of Neuroscience and Basic Behavioral Sciences to: Steven Zalcman, M.D. Division of Neuroscience and Basic Behavioral Sciences National Institute of Mental Health 6001 Executive Boulevard, Room 7177, MSC 9639 Bethesda, MD 20892-9639 Telephone: (301) 443-1692 FAX: (301) 443-4822 Email: szalcman@mail.nih.gov Direct inquiries regarding fiscal matters to: Diana S. Trunnell Grants Management Branch National Institute of Mental Health 6001 Executive Boulevard, Room 6115, MSC 9605 Bethesda, MD 20892-9605 Telephone: (301) 443-2805 FAX: (301) 443-6885 Email: Diana_Trunnell@nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance Nos. 93.242. Awards are made under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and 285) and administered under PHS grants policies and Federal Regulations 42 CFR 52, 45 CFR 66 and 45 CFR 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS strongly encourages all grant and contract recipients to provide a smoke-free workplace and promote the non-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, and 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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