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NIAMS Investigator-Initiated Clinical Trials Policies
Reviewed October 18, 2011
Pilot and Feasibility Clinical Research Grants (R21)
NIAMS Clinical Trial Planning Grants (U34)
NIAMS Clinical Trial Implementation Cooperative Agreement (UM1/U01)
Letter of Request, Application Submission and Review
The NIH defines a clinical trial as a prospective biomedical or behavioral research study of human subjects that is designed to answer specific questions about biomedical (drugs, treatments, devices) or behavioral interventions. Clinical trials range from small first-in-human or tolerability studies to larger trials of efficacy or effectiveness. The NIAMS clinical trials program is designed to support the spectrum of such studies with funding mechanisms tailored to different levels of complexity and risk. Investigators planning trials that involve few subjects and limited duration of follow-up, or needing pilot data for a larger clinical trial, may apply for a NIAMS Pilot and Feasibility Clinical Research Grant (R21). For trials involving greater numbers of subjects or of greater complexity, investigators should apply for funding through a NIAMS Clinical Trial Implementation Cooperative Agreement, with a U01 for a single site trial or a UM1 for a multi-site trial. These larger and more complex trials require substantial planning and preparation prior to opening for recruitment, and, investigators will be expected to apply for a NIAMS Clinical Trial Planning Grant (U34) prior to applying for the UM1/U01 to implement the trial, except when planning and administrative tasks for the trial have been completed through a previous U34 or R34 or other means. The purpose of this policy statement is to summarize these different options. More detail for each will be provided in the individual program announcements for Pilot and Feasibility Clinical Research grants (R21), Clinical Trial Planning Grants (U34), and Clinical Trial Implementation Cooperative Agreements (UM1/U01) through the links below. In addition, this policy will summarize processes and requirements for submission and review of applications.
Pilot and Feasibility Clinical Research Grants (R21)
The Pilot and Feasibility Clinical Research Grants Program is designed to allow initiation of exploratory, short-term clinical studies, intended to facilitate the development of new ideas which may be investigated without stringent requirements for preliminary data. Proposed studies should focus on research questions that are likely to gather critical preliminary data in support of a future, planned clinical trial or to benefit clinical research and trials more broadly, such as by demonstrating the feasibility of a recruitment target or approach, obtaining data in support of potential inclusion and exclusion criteria, or to gather preliminary evidence of efficacy, tolerability and/or toxicity of an available drug, biologic or device in a new population relevant to the NIAMS mission.
Examples include testing of:
- new prevention strategies
- a new application of existing pharmacologic or non-pharmacologic interventions or their unique combination
- a new cost effective or adaptive trial design in a specific population or across populations
- studies intended to expand the science of clinical trials overall
Results generated from this program may lead to critical input into a new clinical trial; trials that inform decision-making in urgent or high priority clinical practice needs for arthritis and musculoskeletal and skin diseases; or preliminary data for trials in understudied and rare diseases. A high priority is the use of such studies to help stimulate the translation of promising research developments from the laboratory into clinical practice. It is expected that pilot and feasibility clinical research grants would provide data needed to support a research project grant application for a full-scale clinical trial, or a large scale observational or epidemiologic study. Rare diseases research groups are especially encouraged to use this mechanism to pilot trials that will need to include multiple institutions to obtain an adequate number of patients.
Basic laboratory research or studies of laboratory animals are not appropriate for this Program Announcement. Studies on blood or tissue samples derived from human subjects, collected independently from the proposed project, will not be supported through this funding mechanism, unless the data derived from the proposed R21 will then be directly applied to an application for a clinical trial or observational study involving human subjects.
NIAMS Clinical Trial Planning Grants (U34)
Clinical research is a significant NIAMS investment aimed at answering critical questions about a particular disease or disease process. The NIAMS will support trials to test promising new interventions with the potential to improve health practices and clinical care. The NIAMS investigator-initiated clinical trials process has been designed to provide funding to assist investigators in completing the required planning and administrative procedures at a reasonable pace so that the conduct of the study, analysis of data, and dissemination of results are not delayed.
The NIAMS has determined that investigator-initiated, interventional clinical trials requesting NIAMS support should undergo a rigorous planning, design, and documentation phase before a decision is made to implement a study with a substantial fiscal and human investment. The implementation of a clinical trial requires extensive preparation (e.g., protocol finalization, manual of operations development, establishing collaborations and estimating recruitment potential) before participant recruitment can occur. It is anticipated that all complex clinical trials will begin with a planning grant. However, if it can be demonstrated that sufficient preparation has occurred such that the trial is ready to move forward to implementation, as defined by NIAMS-specific criteria [see milestones], direct submission of the implementation U01 may be permitted. The NIAMS is offering this two-part process that separates planning and preparation from subject recruitment and study implementation to provide adequate support and facilitate the timely implementation of studies important to the mission of the Institute. In addition, use of the cooperative agreement mechanism will allow NIAMS programmatic input during the early planning stages and throughout the conduct of the actual clinical trial.
The U34 planning grants will give investigators the time and funds necessary to complete detailed clinical study planning to meet NIAMS and NIH standards and regulatory requirements. A structured planning process will allow studies to complete the administrative activities as expeditiously as possible so that the implementation phase (UM1/U01) can start and finish the required activities within a five-year grant period.
The U34 planning grant process is designed to:
- Permit early peer review of the rationale and feasibility of the proposed clinical trial
- Permit optimization of the design of the proposed trial (see below)
- Provide support for the development of a complete study protocol and associated documents and of other essential elements of a clinical trial.
The activities required in the U34 planning grant will depend on the type and complexity of the study (e.g., drug trial, surgical, or behavioral intervention). Please refer to the Program Announcement PAR-11-169 for examples of research activities that are appropriate for a Clinical Trial Planning Grant.
The U34 application is designed to provide the investigators an early review of the rationale and feasibility of the proposed trial. Thus, sufficient details of the clinical trial (such as overall study design, primary objective, inclusion and exclusion criteria, proposed study population, proposed study agent(s), sample size, study end points and duration of recruitment and follow-up) should be included to allow assessment of the feasibility and of the scientific importance and validity of the design. However, U34 funding may be used to complete basic protocol development when activities such as meetings of investigators or consulting experts are required to optimize protocol design. In instances where basic protocol development can only be completed with U34 funding, the application should indicate the advantages of this approach and indicate how the funding will be used to complete the design of the study.
The U34 application should identify clear milestones to be achieved during the planning process. Before an award is made, the NIAMS and the Principal Investigator will agree on the milestones milestones to be completed during the U34 project period and these will be incorporated into the notice of grant award (NoA). Certain of these milestones will be specified as required prior to submission of an application for a U01 to implement the trial. Such milestones are essentially those elements that would need to be completed prior to submitting a proposal for the U01. They will vary with the nature of the trial being planned. The NIAMS is committed to minimizing any delay in implementing the trial, and will work with the investigator to tailor the milestones and duration of the trial preparation phase, supported by the planning grant, so as to proceed as expeditiously as possible to trial implementation, supported by a UM1/U01. This flexibility on the part of the NIAMS will provide for a range of durations of grants, from short, when many milestones have already been met, to the full two-years, when many elements of trial preparation would benefit from a more extensive planning phase. In addition, as discussed above, the NIAMS may accept an application for a UM1/U01 implementation grant without a prior U34 planning grant when all elements of trial preparation are essentially complete (see milestones).
The NIAMS Clinical Trial Planning Grant is not intended to support experimental activities that involve the use of human subjects. However, it may be that prior to submission of a clinical Trial Implementation Cooperative Agreement (UM1/U01), additional data is needed on dosing or other aspects of a trial that would require human subjects. In such cases, investigators should consider the possibility of submitting a Pilot and Feasibility Clinical Research Grant (R21) application to generate that additional data. Pilot and Feasibility Clinical Research Grant (R21) applications may be submitted concurrent with an application for a Clinical Trial Planning Grant (U34) if the results of the Pilot and Feasibility Clinical Research Grant (R21) can be incorporated into the planning process and be used to support an application for a Clinical Trial Implementation Cooperative Agreement (UM1/U01 ).
NIAMS Clinical Trial Implementation Cooperative Agreement (UM1/U01)
Following the completion of designated milestones in the clinical trial planning process, investigators may consider applying for a Clinical Trial Implementation Cooperative Agreement (UM1/U01). The NIAMS will only accept, peer review, and consider funding applications for implementation of investigator-initiated clinical trials from U34 awardees (or previous R34 awardees) when the necessary planning and administrative tasks have been completed. Each clinical trial implementation application will use the SF424 application and(U01) or the PHS 398 (UM1) and will include the clinical protocol, Clinical Investigator's Brochure where appropriate or other equivalent document(s) that contains relevant non-clinical and preclinical data on study products, a Manual of Procedures, and meet all applicable NIAMS, NIH, Food and Drug Administration (FDA), and Office of Human Research Protections (OHRP) policy requirements. FDA Good Clinical Practice guidelines can be found at http://www.fda.gov/oc/gcp/default.htm. Planning grant awardees must prepare their protocols, Clinical Investigators' Brochures, and Manuals of Procedures to meet this guidance (see http://www.niams.nih.gov/Funding/Clinical_Research/NIAMS_guidelines.asp for the NIAMS’s Clinical Protocol and Manual of Procedures guidelines). Information about Institutional Review Board and Independent Ethics Committee (IRB/IEC) registration and assurances is found at http://www.hhs.gov/ohrp/.
A UM1/U01 clinical trial implementation cooperative agreement application should describe all necessary components to successfully conduct a trial. Implementation support is defined as support for activities related to the conduct of the clinical trial, including, but not limited to:
- training of study personnel;
- enrollment and recruitment of study subjects, including women, racial and ethnic minorities, children, and other special populations, as appropriate;
- data collection, management and quality control;
- laboratory work and data analyses;
- study management and oversight;
- establishment of committees to manage the complexity of the trial
- preparation of the final study report; and
- other related post-enrollment activities.
Resources that may be available to support clinical trials during clinical trial implementation can be obtained from the NIAMS program staff. NIAMS clinical research policy and guidance information as well as NIAMS templates are available at the following website: http://www.niams.nih.gov/Funding/Clinical_Research/clinical_main.asp
Examples of studies that might be supported by this FOA include, but are not limited to, clinical trials in arthritis, musculoskeletal and skin disease:
- Testing new therapies or devices;
- Comparing effectiveness of therapeutics or management strategies;
- Testing interventions to promote behaviors that prevent or reduce disease or disease burden
Each NIAMS Clinical Trial Implementation UM1/U01 award will support the implementation of a single clinical trial. Applications that include more than one clinical trial will not be reviewed.
Prior Consultation, Application Submission and Review
Investigators should contact the appropriate NIAMS Program Officer prior to submitting applications for either a U34 clinical trial planning grant or a UM1/U01 implementation grant application. Applicants should refer to http://www.niams.nih.gov/Funding/Clinical_Research/consultation.asp for details on additional information they might wish to share with the Program Officerin a presubmission consultation. In addition, all investigators considering applying for a U34 or a UM1/U01 are strongly encouraged to submit a Letter of Intent (LOI) to the NIAMS before submission of the application, including new and resubmission applications. Applicants are encouraged to allow enough time before the planned receipt date to give the Institute at least 10-weeks to discuss the LOI with the investigators, particularly if there has been no prior consultation with the NIAMS about the application. Instructions as to the contents of the LOI are provided in the Program Announcement. LOI should be submitted to the Scientific/Research contacts listed in the Program Announcement who will share the request with the appropriate Program Officer.
Pre-approval is required prior to submission of an application which will have direct costs of $500,000 or more in any given year, as per NIH policy (see NOT-OD-02-004). Applicants should go to http://www.niams.nih.gov/Funding/Clinical_Research/clinical_letter_request.asp for information about what to include in their Letter of Request (LOR). Applicants should allow enough time before their planned receipt date to give the Institute at least 10 weeks to determine whether it will approve the written request to submit a UM1/U01. NIAMS staff, assisted by a working group of the NIAMS Advisory Council, will consider whether the proposed clinical trial meets the goals and mission of the Institute, and is a high-priority issue within its respective field (likely to improve clinical practice or policy), and whether it is appropriate to conduct it as an investigator-initiated clinical trial. The NIAMS will not evaluate the technical and scientific merit of the proposed trial at this stage. Technical and scientific merit will be determined during peer review. Applicants whose projects do not meet NIAMS’ programmatic needs or are not considered to be appropriate as investigator-initiated clinical trials will not be granted permission to submit an application. Pre-approval by NIAMS, on the basis of an LOR submitted prior to the application, indicates that NIAMS has determined that the proposed project is of high priority. An approval letter to submit the application may be obtained from the appropriate NIAMS Division Director and should be included with the application.
Peer review of properly completed applications submitted in response to the Program Announcements for the clinical trials R21, U34 and UM1/U01 will be conducted by the NIAMS AMS Clinical Trials Review Committee. This review committee will provide expertise in NIAMS disease areas and in clinical trial methodology, continuity of review, and improved coordination with NIAMS.
The NIAMS will make funding decisions on investigator-initiated clinical trials applications with meritorious scores based on programmatic priority. Those judged to have low program priority, or that fail to meet the criteria outlined above, will not receive funding, even if found to be scientifically sound in peer review.
This policy only applies to applications submitted in response to the Funding Opportunity Announcements for the clinical trial R21, U34 and UM1/U01. Grant applications that propose clinical trials submitted in response to a Request for Applications (RFA) and contract proposals for clinical trials submitted in response to a Request for Proposals (RFP) will follow the guidelines and instructions in the RFA or RFP, respectively.
Any applications dealing with mechanistic studies in clinical trials of immunomodulatory interventions for immune-mediated diseases should be submitted to the NIAID Hyperaccelerated Award Program for Ancillary Studies in Immunomodulation Clinical Trials (RFA-AI-10-014) in which NIAMS is a participating institute. Investigators should consider RFA-AR-10-011 for ancillary studies that are exploratory/developmental and highly innovative in nature and related to the NIAMS mission. Such studies must be in conjunction with privately or publicly funded, large, ongoing clinical projects and meet time-sensitivity requirements.