NIAMS Investigator-Initiated Clinical Trials Policies

Updated October 4, 2016

Introduction
Exploratory Clinical Trial Grants (R21)
Clinical Observational (CO) Studies in Musculoskeletal, Rheumatic, and Skin Diseases (R01)
NIAMS Clinical Trial Planning Grants (R34)
NIAMS Clinical Trial Implementation Cooperative Agreement (U01)
Prior Consultation, Application Submission and Review
Applications with Direct Costs of $500,000 or Greater in Any Year
Other FOAs

Introduction

The NIH defines a clinical trial as a research study in which one or more human subjects are prospectively assigned to one or more interventions (which may include placebo or other control) to evaluate the effects of those interventions on health-related biomedical or behavioral outcomes. Clinical trials range from small first-in-human, tolerability or exploratory 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 short-term studies that involve few subjects and limited duration of follow-up with the goal of collecting experimental data needed to launch a future clinical trial may apply for a NIAMS Exploratory Clinical Trial Grant (R21) or a Clinical Observational (CO) Studies in Musculoskeletal, Rheumatic, and Skin Diseases (R01) grant. For trials involving a larger number of subjects or that are more complex, the NIAMS supports investigator-initiated, interventional clinical trials through a Clinical Trial Implementation Cooperative Agreement (U01). While these trials often involve a larger number of subjects, more clinical sites or are deemed more complex than a R21 or R01, there are no hard-and-fast requirements regarding either sample size or research design for any of these funding mechanisms.

This policy statement summarizes these different options. More detail for each will be provided in the individual program announcements for Exploratory Clinical Trial Grants (R21), Clinical Observational Studies in Musculoskeletal, Rheumatic and Skin Diseases (R01) grants, Clinical Trial Planning Grants (R34), and Clinical Trial Implementation Cooperative Agreements (U01) through the links below. In addition, this policy summarizes processes and requirements for submission and review of applications.

Exploratory Clinical Trial Grants (R21)

PAR-14-192

The Exploratory Clinical Trials Grants Program is designed to facilitate the execution of short-term interventional studies to obtain the experimental data needed to launch future clinical trials. The purpose of the Program is to foster the development and implementation of interventional exploratory clinical trials aimed at providing clinically meaningful improvements in symptoms, function or disease course for patients with rheumatic, musculoskeletal or skin diseases. The trials must address research questions related to the mission and goals of the NIAMS. Trials may evaluate drugs, biologics, devices, or surgical, dietary, behavioral or rehabilitation therapies.

The proposed trials should strive to investigate new ideas and may use novel trial designs to focus on research questions that have the potential to contribute critical, clinically-relevant data in support of a future, more robust clinical trial, or that can impact clinical decision making at the patient level. The objectives of the trial may require a more flexible (i.e., adaptive) approach to design so that changes can be made in response to accumulating results, and the analysis may entail data exploration that is pre-specified in the protocol. The rationale for the proposed exploratory study should be supported by strong preclinical data. However, preliminary data specifically related to clinical effect of the proposed intervention in the targeted condition are not required for R21 applications although it may be included if available.

Proposed studies are expected to generate data to support future clinical trials or patient care by gathering evidence of a clinically-meaningful improvement in the efficacy, tolerability, dose response, and/or toxicity of a new or available therapeutic intervention (or their combination) in a population relevant to the NIAMS mission.

Examples of research areas covered by this Program include:

  • Conducting first-in-human, pilot clinical trials (previously developed and assessed through in vitro studies, animal testing or modeling, but not yet tested in humans).
  • Conducting safety/tolerability/dose/efficacy trials with drugs, biologics and devices approved for treatment of other diseases/disorders, or dietary supplements for arthritis, musculoskeletal or skin disease symptoms and functional improvement.
  • Testing of a new formulation or delivery device for a new or repurposed agent.
  • Conducting trials to implement novel, clinically relevant strategies for arthritis, musculoskeletal or skin disease symptoms and functional improvement. to address racial, ethnic, geographic, or socioeconomic outcome disparities in underserved and minority populations Addressing issues in special populations (e.g., pediatric patients), including pain, psychosocial adjustment, and physical functioning.
  • Performing early intervention trials designed to identify novel means to prevent onset, slow progression and/or reduce the burden of symptoms of disease.
  • Conducting trials studying new approaches to preventing disease onset
  • Conducting feasibility clinical trials that focus on novel, cost-effective treatments for rare diseases.
  • Application of adaptive trial design in a specific population or across populations.

Basic laboratory research or studies of laboratory animals are not appropriate for this Program Announcement. PDs/PIs who are seeking support only for drug development and do not have access to medicinal chemistry and drug development expertise are encouraged to consider other programs for those areas which are available through individual NIH Institutes. Note that the Bridging Interventional Development Gaps (BrIDGs) (https://ncats.nih.gov/bridgs), previously the NIH Rapid Access to Interventional Development (NIH-RAID) Program (www.nihroadmap.nih.gov/raid), offers investigators access to Investigational New Drug (IND)-directed services on a competitive basis. Investigators who are seeking support for such studies are encouraged to apply there.

Clinical Observational (CO) Studies in Musculoskeletal, Rheumatic, and Skin Diseases (R01)

PAR-15-115

This Funding Opportunity Announcement (FOA) is to encourage Research Project Grant (R01) applications to pursue clinical observational (CO) studies. The purpose of such a research project is to obtain data necessary for designing clinical trials for musculoskeletal, rheumatic, or skin diseases or conditions. Research data from observational cohort studies can enhance clinical trial design by providing essential information about disease symptoms, stages and timing of disease progression, comorbid conditions, availability of potential clinical trial participants, and outcomes that are important to patients. CO studies also can facilitate efforts to develop and/or validate objective biomarkers or subjective outcome measures for use in a future trial or trials. Applicants to this FOA are encouraged to propose studies that address significant obstacles or questions in the design of a clinical trial, such as determining the appropriate primary or secondary outcome measures, or identifying the stages of disease during which patients are most likely to respond to an intervention. This initiative will support observational studies only, and will not support interventional studies, also called clinical trials Specific examples of research areas of interest include but are not limited to:

  • Characterizing the frequency and/or severity of disease symptoms that would be measured as an outcome in a future trial.
  • Correlation studies comparing a biochemical or imaging biomarker to other, established outcome measures in order to establish surrogate markers.
  • Testing clinical study recruitment strategies for patients with rare disease and/or who are members of underserved populations who could be candidates for participating in a future clinical trial.
  • Collecting adverse event information during standard of care administration in an observational study setting to be included in the design (e.g., inclusion/exclusion criteria, investigator's brochure) for a future clinical trial.
  • Collecting standard of care data in an observational study setting to be used as a historical control for a future clinical trial.

NIAMS Clinical Trial Planning Grants (R34)

PAR-16-446

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 resource investment. The implementation of a clinical trial requires extensive administrative planning (e.g., protocol finalization, manual of operations development, establishing collaborations and estimating recruitment potential) before participant enrollment can occur. The R34 planning grants will give investigators the time and funds necessary to complete detailed clinical trial planning to meet NIAMS and NIH standards and regulatory requirements. A structured planning process will allow studies to determine the optimal design strategy and to complete the administrative activities as expeditiously as possible so that time is not spent during the implementation phase (U01) completing such activities.

The R34 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
  • 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 R34 planning grant will depend on the type and complexity of the study (e.g., drug trial, surgical, behavioral intervention, or multi-site or single-site). Please refer to the Program Announcement PAR-16-446 for examples of research activities that are appropriate for a Clinical Trial Planning Grant.

The R34 application is designed to provide the investigators an early review of the rationale for the proposed clinical trial and to provide support for the applicant to establish the research team, develop tools for data management and oversight of the research, define recruitment strategies, develop and finalize the clinical protocol and all essential elements of the study required for the clinical trial including all the appropriate documents.

The R34 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 to be completed during the R34 project period, and these milestones will be incorporated into the notice of grant award (NoA). Completion of certain milestones will be required prior to submission of an application for a U01 to implement the trial and 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 quickly to trial implementation, supported by a U01. This flexibility will allow 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 U01 implementation grant without a prior R34 planning grant if all elements of trial preparation are complete (see milestones).

The NIAMS R34 is intended to support necessary administrative study activities before recruitment of subjects into the future clinical trial begins. The R34 cannot be used to recruit human subjects. In addition, it cannot be used to collect data on research participants unless those data are only for the purpose of testing recruitment strategies on a potential pool of interested and eligible subjects (e.g., through conducting “model recruitment” using focus groups, surveys, questionnaires, etc.). In cases where additional data is needed on dosing or other aspects of a trial that would require human subjects, investigators should consider submitting an Exploratory Clinical Trial Grant (R21) application or a Clinical Observational (CO) Studies in Musculoskeletal, Rheumatic, and Skin Diseases (R01) grant to generate that additional data. If substantial preliminary data are needed to support the Clinical Trial Implementation grant (U01), it is suggested the R21 or CO R01 grant be submitted prior to the R34 submission.

See more at: http://grants.nih.gov/grants/guide/pa-files/PAR-16-446.html

NIAMS Clinical Trial Implementation Cooperative Agreement (U01)

PAR-16-447

Following the completion of designated milestones in the clinical trial planning process, investigators may consider applying for a Clinical Trial Implementation Cooperative Agreement (U01). The NIAMS will only accept, peer review, and consider funding applications for implementation of investigator-initiated clinical trials when the necessary planning and administrative tasks have been completed. Normally applications to the NIAMS go through a two-part process, which begins with a R34 planning grant (Part 1) followed by an application for the U01 (Part 2). Investigators who have completed all necessary pre-trial planning and preparation through other means may apply for a NIAMS U01 without having applied for a R34. Clinical trials must also meet all applicable NIAMS, NIH, Food and Drug Administration (FDA), and Office of Human Research Protections (OHRP) policy requirements.

A 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 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: https://www.niams.nih.gov/Funding/Clinical_Research/NIAMS_guidelines.asp

Examples of studies that might be supported by this Funding Opportunity Announcement include, but are not limited to:

  • Clinical trials focusing on the prevention or treatment of a rheumatic, musculoskeletal or skin disease or disorder;
  • Clinical Trials to investigate safety, efficacy, or effectiveness of novel therapeutic approaches for one or more of these conditions;
  • Clinical trials testing methods to increase preventive health behaviors for one or more of these conditions.

Each NIAMS Clinical Trial Implementation 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 a NIAMS Exploratory Clinical Trial (R21) grant, a NIAMS Clinical Observational (R01) grant, a NIAMS R34 clinical trial planning grant or a U01 implementation grant application. Applicants should refer to https://www.niams.nih.gov/Funding/Clinical_Research/clinical_consultation.asp for details on additional information they might wish to share with the Program Officer in a pre-submission consultation. Pre-approval is required prior to submission of an application that will have direct costs of $500,000 or more in any given year. Potential applicants must submit an LOR to the NIAMS at least 10 weeks prior to the application due date. See https://www.niams.nih.gov/funding/clinical_research/clinical_letter_request.asp for LOR requirements. All investigators considering applying for a R34 or a U01 with budgets less than $500,000 in any given year 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 sufficient time to discuss the LOI or LOR 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. The LOI should be submitted to the Scientific/Research contact listed below who will share the request with the appropriate Program Officer.

LOI Submission:

Shahnaz Khan, MPH
Telephone: 301-451-9893
Fax: 301-480-4543
Email: Khanshah@mail.nih.gov

Peer review of properly completed applications submitted in response to the Program Announcements for a NIAMS clinical R21, R01, R34 and 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.

Applications with Direct Costs of $500,000 or Greater in Any Year

Per NIH policy, pre-approval is required prior to submission of an application that will have direct costs of $500,000 or more in any given year. Applicants should refer to NIAMS specific guidelines for information about deadlines and what to include in their Letter of Request (LOR) seeking permission to submit an application (see https://www.niams.nih.gov/Funding/Clinical_Research/clinical_letter_request.asp). Potential applicants must submit the LOR at least 10 weeks prior to the application due date to determine whether the Institute will approve the written request to submit a U01. 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. The NIAMS will inform the applicant by email of the decision.

Other FOAs

This policy only applies to applications submitted in response to the Funding Opportunity Announcements for a NIAMS clinical R21, R01, R34 and U01 described above. Applicants who propose clinical trials submitted in response to other funding opportunity announcements will follow the guidelines and instructions in those announcements. Exclusions of clinical trials under those announcements may apply.

Investigators seeking support only for drug development and who do not have access to medicinal chemistry and drug development expertise are encouraged to consider other programs for those areas which are available through individual NIH Institutes. Note that the Bridging Interventional Development Gaps (BrIDGs) (https://ncats.nih.gov/bridgs), previously known as the NIH Rapid Access to Interventional Development (NIH-RAID) Program), offers investigators access to IND-directed services on a competitive basis. Investigators who are seeking support for such studies are encouraged to apply there. The NCATS Therapeutics for Rare and Neglected Diseases (TRND) program is designed to encourage and speed the development of new drugs for rare and neglected diseases. TRND stimulates drug discovery and development research collaborations among NIH and academic scientists, nonprofit organizations, and pharmaceutical and biotechnology companies working on rare and neglected illnesses. PDs/PIs are encouraged to refer to https://ncats.nih.gov/trnd to determine if there are opportunities offered through this program that suits their needs.