ANCILLARY STUDIES ON CONTROL GROUPS IN CLINICAL TRIALS RELEASE DATE: April 3, 2002 PA NUMBER: PA-02-094 EXPIRATION DATE: February 2, 2005, unless reissued. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (http://www.niddk.nih.gov/) National Center for Complementary and Alternative Medicine (NCCAM) (http://www.nccam.nih.gov/) THIS PA CONTAINS THE FOLLOWING INFORMATION o Purpose of the 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 OF THIS PA The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the National Center for Complementary and Alternative Medicine (NCCAM) invites grant applications for ancillary studies to NIH funded interventional clinical trials to address the biological, behavioral and statistical issues related to the control or comparison group used in these trials and the effects of inclusion of a placebo group on clinical trial design.. The NIDDK/NCCAM cosponsored workshop "The Science of the Placebo: Toward an Interdisciplinary Research Agenda"(http://placebo.nih.gov), held November 19-21, 2000 on the NIH campus emphasized that the use of placebos as controls in research designed to assess the efficacy of therapeutic or preventive agents is a complex issue. Applications are sought which utilize the patient populations in existing or planned NIH clinical trials to address key unresolved questions in clinical trial design about the control group. Applications responsive to this solicitation would examine such questions as: the magnitude of placebo effects on various types of outcome measures and at various times after initiation of the intervention; the assessment by potential trial participants or referring physicians of benefits and risks of trial participation; the impact of placebo and active control groups on recruitment; the effectiveness of blinding and the perception of patients and/or investigators on trial group membership and correlation with effect. RESEARCH OBJECTIVES Background: A control group receiving placebo treatment is often used in clinical trials to assess the efficacy of the study intervention. This use of placebo controls has raised a number of ethical, philosophical, statistical and trial design issues. Many of these issues were highlighted at the National Institutes of Health workshop "Science of the Placebo: Towards and Interdisciplinary Research Agenda" held in November 2000 (http://placebo.nih.gov). There is broad unanimity in the principle that in the conduct of clinical trials the inclusion of a placebo group is compatible with equipoise when there is no established treatment available. Implementation of this principle, however, requires complex judgments of benefit and risk about which there is frequently not general agreement. A more rigorous basis is needed to inform the selection of the appropriate control group in clinical trials. Objectives: The purpose of this PA is to fund studies which will utilize the patient populations in existing NIH funded clinical trials to address the numerous issues and unresolved questions in clinical trial design which are involved in selecting and using a control group in clinical trials. Appropriate topics for investigation would include, but are not limited to: - studies to determine how potential participants and referring physicians approach risk/benefit assessment; - studies which address the anticipated impact of the magnitude of the placebo effect on trial design at various time points and with various study instruments; - the use of control groups in surgical interventions; - the magnitude of the placebo effect in various diseases; - the relationship between the size of the placebo effect and outcome measures, especially those which use patient self report of response to therapy; - the relationship between placebo effect and regression to the mean; - the duration of the placebo effect; - patient factors that are predictive of the magnitude of the placebo effect; -the effectiveness of blinding and the perception of patients and/or investigators on trial group membership and correlation with effects; -studies to determine the most effective placebo and comparison arms in clinical trials that are evaluating the efficacy of complex systems of medicine, holistic therapies, or complementary and alternative medicine (CAM) modalities such as chiropractic and acupuncture. It is anticipated that the results of the studies funded through this PA will provide new insights into the role of the placebo and control group in clinical trials and will provide better methods for trial design and analysis. MECHANISM OF SUPPORT This PA will use the National Institutes of Health (NIH) research project grant (R01) award and the exploratory/developmental grant (R21) mechanism. The purpose of the R21 award mechanism is to demonstrate feasibility and obtain preliminary data. These grants will not be renewable; continuation of these projects will be through the regular research grant (R01) mechanism. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The total project period for an application submitted in response to this PA may not exceed five years for R01 projects and two years for R21 projects. R21 applications cannot exceed $125,000 in direct costs per year. R01s greater that $250,000 per year require detailed budgets. This PA uses just-in-time concepts. It also uses the modular as well as the non-modular budgeting formats (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. Otherwise follow the instructions for non-modular research grant applications. Ancillary studies to both U01, R01, and P50 (NCCAM only) funded trials will be accepted. Ancillary studies to trials funded as U01s will require written approval by the institute Program Officer. Studies for trials funded as R01s and P50s will require written approval from the Principal Investigator of the trial. 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 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. Inquiries may fall into three areas: scientific/research, peer review, and financial or grants management issues: o Direct your questions about scientific/research issues to: for NIDDK: Leroy M. Nyberg, Jr., Ph.D., M.D. Division of Kidney, Urologic, and Hematologic Diseases National Institutes of Diabetes and Digestive and Kidney Diseases 6707 Democracy Boulevard, Rm. 627 MSC-5458 Bethesda, MD 20892-5458 Telephone: (301) 594-7717 FAX: 301-480-3510 E-mail: ln10f@nih.gov for NCCAM: Nancy J. Pearson, Ph.D. Program Officer National Center for Complementary and Alternative Medicine 6707 Democracy Blvd, Room 106, MSC-5475 Bethesda, MD 20892-5475 Telephone: (301) 594-0519 Fax: (301) 480-3621 E-mail: pearsonn@mail.nih.gov o Direct inquiries about financial or grants management matters to: NIDDK: Trude Hilliard Grants Management Branch Division of Extramural Activities National Institutes of Diabetes and Digestive and Kidney Diseases 6707 Democracy Boulevard, Rm. 717, MSC 5456 Bethesda, MD 20892 Telephone: (301) 594-8859 Fax: (301) 480-3504 E-mail: th105x@nih.gov NCCAM: Victoria Carper Grants Management Officer National Center for Complementary and Alternative Medicine 6707 Democracy Blvd, Rm 106, MSC-5475 Bethesda, MD 20892 Telephone: 301 594 9102 FAX: 301 480 3621 Email: carperv@mail.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 R21 APPLICATIONS: All application instructions outlined in the PHS 398 application kit are to be followed, with the following requirements for R21 applications: 1. R21 applications will use the "MODULAR GRANT" and "JUST-IN-TIME" concepts, with direct costs requested in $25,000 modules, up to the total direct costs limit of $100,000 per year. 2. Although preliminary data are not required for an R21 application, they may be included. 3. Sections a-d of the Research Plan of the R21 application may not exceed 15 pages, including tables and figures. 4. R21 appendix materials should be limited, as is consistent with the exploratory nature of the R21 mechanism, and should not be used to circumvent the page limit for the research plan. Copies of appendix material will only be provided to the primary reviewers of the application and will not be reproduced for wider distribution. The following materials may be included in the appendix: Up to five publications directly relevant to the project. Surveys, questionnaires, data collection instruments, and clinical Protocols. These may be stapled as sets. Original glossy photographs or color images of gels, micrographs, etc., provided that a photocopy (may be reduced in size) is also included within the 15 page limit of items a-d of the research plan 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. Applicants must define, in their application, the specific clinical trial by grant number(s), trial title, and Principal Investigator and/or Steering Committee Chairperson, for which they are proposing an ancillary study. They must also include in the application a signed letter from either the Program Officer (for U01 clinical trials) or the Principal Investigator approving the concept and cooperation in the study. Applicants must include in the appendix to the application copies of the relevant grant or clinical trial protocol, so that reviewers can understand the context of the proposed study. 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 NIH staff member within one of NIH institutes or centers 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 on or 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, animals, 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. AWARD CRITERIA Applications submitted in response to a program announcement will compete for available funds with all other recommended applications. The following will be considered in making funding decisions: o Quality of the proposed project as determined by peer review; o Availability of funds; o Program priority. REQUIRED FEDERAL CITATIONS 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_20 01.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 an NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site. HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This 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. This program is described in the Catalog of Federal Domestic Assistance No. 93. 93.849 and 93.213 Awards are 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 NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. 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, 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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