Funding

Clinical Research

Updated September 10, 2007

Guidelines for Submission of Applications for Investigator-Initiated Clinical Trials

  1. Purpose of this Document
  2. Institute Acceptance of Applications
  3. Application Format
  4. Data and Safety Monitoring
  5. Institute Staff Involvement
  6. Reporting Requirements
  7. NIAMS Review of the Application
  8. Submission of Application

A. Purpose of This Document

This document outlines the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) policy and procedures for investigator-initiated clinical trials and provides guidelines for the preparation and submission of these applications. It lists the requirements placed on the receipt, review, and funding of these applications and presents guidelines for the conduct of such trials. This is not a solicitation for such applications. These guidelines apply to investigator-initiated clinical trials irrespective of the grant mechanism being used (e.g., R01, P01, P50, P60, etc.). An application for a clinical trial should be submitted as a whole rather than applications from individual sites or components. Clinical trials submitted as projects in a P50 (Specialized Center of Research) or P60 (Multidisciplinary Clinical Research Center) should follow the application format described in these guidelines (Section C) and include a discussion of data safety and monitoring (Section D).

B. Institute Acceptance of Applications

Applications for support of investigator-initiated clinical trials must be submitted to NIH through its Center for Scientific Review (previously called The Division of Research Grants). All multicenter (defined as three or more clinical sites) and some applications with fewer sites, will be assigned for initial review by an ad hoc Special Emphasis Panel (SEP) managed by NIAMS's Review Branch. The application will be assigned to the appropriate NIAMS Program for scientific administration and management.

Because NIAMS staff must consider other factors in addition to scientific merit in funding clinical trial grants, it is in the best interest of potential applicants to consult with NIAMS staff prior to submission of new, renewal, or supplemental applications. The consultations serve to clarify whether the program will fit the criteria of a clinical trial, the mission of the NIAMS, and any fiscal or additional constraints. Current NIH policy (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-004.html) indicates that an applicant planning to submit an investigator-initiated grant application requesting $500,000 or more in direct costs for any year must contact institute program staff before submitting the application, i.e., as plans for the study are being developed. Furthermore, the applicant must: (a) obtain agreement from Institute (NIAMS) program staff that NIAMS will accept the application for consideration; and (b) identify, in the cover letter sent with the submitted application, the NIAMS program staff member who agreed to accept assignment of the application. This new policy requires an applicant to obtain agreement for acceptance of any new (Type 1), renewal (Type 2), or supplemental (Type 3) application and any subsequent amendment. Any application subject to this policy that does not contain the required information in the cover letter sent with the application will be returned to the applicant without review.

Thus, a letter describing the proposed clinical trial to a NIAMS Program Director, at least four months before submission, is needed to facilitate Institute planning and allow Institute approval for submission of the grant. Ideally, this letter would include a brief description of the clinical trial, the particular projects to be proposed in the grant application, a list of key participants, and approximate direct costs. Applicants should not construe advice given by the staff as assurance of favorable review. The staff will not evaluate or discuss the scientific merit of the proposal.

One of the persons listed below should be contacted for information about the requirements for obtaining approval to submit an application in excess of $500,000 per year in direct costs or to discuss any other issues regarding submission of a clinical trial application.

Program Contact Person Telephone
Behavioral and Prevention Research Program Dr. Susana Serrate-Sztein (301) 594-5032
Center Mechanisms
  • Multidisciplinary Clinical Research Centers (MCRC) P60
 Ms. Justine Buschman (301) 496-4811
  • Centers of Research Translation (CORT) P50
 Ms. Justine Buschman (301) 496-4811
  • Research Core Centers P30
    • Rheumatic Diseases
 Dr. Susana Serrate-Sztein (301) 594-5032
    • Musculoskeletal Disorders
 Dr. Joan McGowan (301) 594-5055
    • Skin Diseases
 Dr Carl Baker (301) 594-5017
Osteoarthritis Initiative and Diagnostic Imaging Program Dr. Gayle Lester (301) 594-5055
Muscle Disorders and Therapies Program Dr. Glen Nuckolls (301) 594-5055
Bone Diseases Program Dr. Joan McGowan (301) 594-5055
Musculoskeletal Development, Tissue Engineering, and Regenerative Medicine Program Dr. Fei Wang (301) 594-5055
Muscle Development and Physiology Program Dr. Amanda Boyce (301) 594-5055
Keratinocyte Biology and Disease Program Dr. Carl Baker (301) 594-5032
Skin Immunobiology and Immune Diseases Program Dr. Cheryl Lapham (301) 594-5032
Systemic Autoimmune Disease Biology Program Dr. Marie Mancini (301) 594-5032
Orthopaedics Program Dr. James Panagis (301) 594-5055
Division of Skin and Rheumatic Diseases Dr. Susana Serrate-Sztein (301) 594-5032

Receipt dates for clinical trial grant applications are established by the Center for Scientific Review (CSR). The receipt dates are February 1, June 1, and October 1 for all clinical trial grant applications, including new, competing continuation, supplemental, and revised applications. The original and five signed, exact, clear, single-sided photocopies of the completed application should be mailed to the Center for Scientific Review (CSR) at the address listed in Form PHS 398.

C. Application Format

The standard PHS 398 Grant Application Form (http://grants1.nih.gov/grants/funding/phs398/phs398.html) is used to apply for investigator-initiated clinical trials. Investigators should adhere to the guidelines detailed in the PHS 398 application kit.

Clinical trials often require the collaboration of multiple field centers, and may include separate data coordinating centers and core facilities. The need for separate centers and cores must be carefully and completely described and justified. Separate budget justifications, facility statements, and informed consent forms must be submitted for each center. Commitment from the principal investigators and business offices of each center must be documented.

The information provided in the application should be organized in a manner that will facilitate peer review. Therefore, it must directly address the stated review criteria. The body of the application must present an overview of the statement of the science, current status, and relevance of the trial, along with a discussion of the specific protocol and approach to data collection and analysis. Details of the protocol, methods, quality control procedures, power analysis, data analysis, and similar material should appear, when needed for a thorough discussion, in well-organized and referenced appendices.

All applications must provide detailed scientific and operational plans as well as funding needs for the entire trial and data analysis period. If the complete trial will take longer than 5 years, please define what will be accomplished in the 5-year period and describe briefly the needs beyond 5 years. The review of the application will evaluate the entire project. It is likely that submission of a competing continuation application will be required to support activities beyond an initial 5-year period.

Investigators must submit a total overall budget and a complete, itemized individual budget for each year of support requested. Separate itemized budgets must be prepared for each subcontract and/or for each center or core for each year, if multiple centers or cores are proposed. All costs requested and all changes in budgets after the first year should be clearly identified and justified. Further information concerning budget preparation may be obtained from the Chief, Grants Management Branch, Extramural Program, NIAMS.

The following sections must be included in the grant application:

1. Specific Aims

The specific aims of the trials must be clearly and concisely presented. These should include a clear specification of the primary and major secondary endpoints to be measured with a clear differentiation of the importance of various endpoints.

2. Significance

The significance of the proposed clinical trial must be clearly stated. It is particularly important that there be a discussion of how the trial will test the hypothesis proposed. The application should make clear the need for the study with emphasis on how the results will advance our knowledge of theory and practice in this area. Where appropriate, costs versus benefits analysis of the trial should be included.

3. Preliminary Studies

The studies that led to the proposed clinical trial should be presented. Data from pilot studies which show the need for such a trial or show the feasibility of the trial should also be presented. Additional supporting data from other research should be included so that the approach chosen is clearly justified. Conceptualization and planning must have progressed to a stage sufficient to allow for an overall assessment of the likelihood of the success of the trial.

4. Experimental Design and Methods

  • Detailed Clinical Protocol

Inclusion and exclusion criteria must be listed and the procedure to be utilized for assignment of patients to experimental conditions described. Detailed study design for the intervention(s) to be used, including the rationale for the particular design chosen, procedures to assure compliance with, and standardized implementation of the proposed protocol should be discussed. Potential biases in the research protocol proposed and how they will be addressed must be described. Clinical (including behavioral and observational), laboratory, and physiological tests and procedures should be described briefly in this section and in more detail in an appendix. Methods of randomization must be described and endpoints clearly defined. Assumptions and steps used to arrive at the proposed sample size must be described. Details of the sample size calculations, when needed for a thorough discussion, should be presented in an appendix.

  • Patient Availability and Recruitment

The availability of patients for the proposed study should be addressed and the characteristics of this population and why it is an appropriate group to answer the question posed should be discussed. The approaches for the recruitment, retention and follow-up of the required number of patients must be outlined. Plans for maintaining the cooperation of the study populations and plans for addressing any anticipated changes in the composition of the study population over the course of the trial should be presented. Competing studies in the same catchment area that may impact the recruitment and retention of patients should be addressed and include data to support recruitment and retention estimates.

  • Data Management, Quality Control, and Data Analysis

The approach to data management must be described and include methods for monitoring the quality and consistency of the intervention(s) and data collection. Prototypes of data collection forms should be included in an appendix. The methods of data analysis, linking the analyses to the hypotheses to be tested must be described and include methods of data preparation and presentation, analytic methods, and approaches to data synthesis. Primary and secondary endpoints should be clearly defined, justified and related to the power of calculations.

5. Human Subjects

Assurances of the protection of human participants and the biohazard safety of employees (if applicable) must be provided both for the overall study and for individual clinical centers. Any issues that might lead to concern for the welfare of subjects should be addressed and all forms to be used to obtain informed consent at each center must be included in an appendix. At a minimum, the human subjects section of the data coordinating center application must address data security measures and confidentiality. (See PHS Form 398 for detailed instructions concerning content of the human subjects section of the application.) The Institutional Review Board (IRB) approvals, if not available at the time of submission, must be submitted prior to funding.

6. Women, Children and Minority Subjects

Women, minorities, and children should be included in the study population in accordance with NIH requirements. See http://grants.nih.gov/grants/funding/women_min/women_min.htm for policies on inclusion of women and minorities and http://grants.nih.gov/grants/funding/children/children.htm for policies on inclusion of children. Specific goals for women, children, and minority recruitment and plans for achieving those goals must be explicitly stated in a separate section of the application. Approximate numbers of women and each minority group expected in the study sample and the basis for these estimates must be provided. Generally, representation of women, children, and minorities will not be considered adequate unless they occur in the study population in the same proportions as the U.S. population with the disease being studied. It is recognized that this may require oversampling.

7. Study Organization and Administration

An outline of a Manual of Operations and Procedures http://www.niams.nih.gov/Funding/Policies_and_Guidelines/MOOP_guidelines_2007.doc must be provided. The organization of the study and how the trial will be managed should be described and include a description of the data safety and monitoring plan, the role of any internal or external advisory committees, including the data safety monitoring committee or officer, the responsibility and authority of the director of the data coordinating center, and policies and methods concerning blinding of study results. The coordination of any centers or cores proposed must be discussed and include a complete description of any subcontracts for personnel or facilities. Documentation of commitment, co-signed by a business official and the principal investigator at the participating center, must be included with the application. A timetable for completion of the various stages of the trial should also be included.

8. Investigators

The overall clinical trial must be directed by an investigator with experience in the conduct of clinical trials and expertise in the content of the trial. Such experience must be carefully documented. Biographical sketches for all key investigators must be provided. Most clinical trial designs will require a multidisciplinary team.

Each center or core proposed must have a director designated. The experience of each director must be carefully documented. In addition, the authority of each center or core director within the study must be specified.

9. Biographical Sketch with Other Support

A biographical sketch that includes other support information must be provided for all key personnel. Key personnel are individuals who contribute in a substantive way to either the scientific development or execution of the project. Key personnel will often include non-doctorate level individuals, such as nurse coordinators.

10. Facilities

Clinical, data management, and laboratory facilities and required equipment should be described in detail for all participating institutions.

11. Budget

A total overall budget and a complete justified budget for each year of support must be prepared. If the trial is designed for more than a five-year period, complete, justified budgets for the future years also must be included. If the study involves multiple centers, additional separate and complete budgets must be prepared for each center. If part of the costs of the trial is to be borne by sources other than NIH, these contributions should be presented in detail along with supporting letters signed by individuals who have the authority to commit the institution. Further information concerning budget preparation can be obtained from the Chief of Grants Management Branch, NIAMS.

D. Data and Safety Monitoring

It is the policy of the NIH (NIH Policy for Data and Safety Monitoring http://grants.nih.gov/grants/guide/notice-files/not98-084.html released on June 10, 1998) that all NIH-sponsored or -conducted clinical trial monitoring activities should be commensurate with the nature, size, and complexity of the trial. In addition, the NIH requires that NIAMS be responsible for oversight of data and safety monitoring, ensuring that monitoring system is in place, it is appropriate for a study, and the Institute is informed of recommendations emanating from monitoring activities.
Investigators must submit a monitoring plan for all clinical trials as part of the research application. This plan will be reviewed by the scientific review group and any comments and concerns will be included in an administrative note in the summary statement. The data and safety monitoring plan may vary from a safety officer to a committee, also known as a data and safety monitoring board (DSMB). All large-scale, complex, or multicenter clinical trials (often Phase III) will need a DSMB. Any high risk Phase I or II clinical trial will also require a DSMB (Further Guidance on Data and Safety Monitoring for Phase I and Phase II Trials http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html released on June 5, 2000). The safety officer will be appointed by the grantee institution and approved by NIAMS. For the DSMB, the grantee institution will have input into the selection of members but the members will be appointed by NIAMS. The DSMB will consist of individuals who are independent of the institution(s) and investigator(s) participating in the trial. DSMB members must have no financial ties to the outcome of the trial to avoid any conflicts of interest. The names of potential DSMB members should not be included in the monitoring plan, however, the type of expertise required should be listed. This ongoing review of the data by an independent individual or committee assures the investigators that the trial can continue without jeopardizing patient safety.
Data and Safety Monitoring Guidelines for Investigator-Initiated Clinical Trials developed by NIAMS may be found at: http://www.niams.nih.gov/Funding/Clinical_Research/guidelines_monitoring_plan.doc.

E. Institute Staff Involvement

Before making an award for an investigator-initiated clinical trial, NIAMS will routinely consider the desirability of substantial continued staff involvement in an assistance mode. If such involvement is deemed appropriate by the Institute, the award mechanism may be converted to a cooperative agreement. Regardless of the mechanism of support, the NIAMS staff will closely monitor progress during the award. This monitoring may include regular communications with the principal investigator and staff, as well as attendance at the steering committee, data safety monitoring board, and related meetings. As with any award, continuation, even during the period recommended for support, is conditional upon satisfactory progress. NIAMS retains, as an option, periodic external peer review of progress.

F. Reporting Requirements

Recruitment progress, indices of quality control, and related operational features must be reported at regular intervals to the NIAMS program office. Annual and final reports are required as with any grant. Annual gender and minority tracking reports are required. In addition, registration of the clinical trial on the NIAMS clinical trial database is required within 21 days of funding. The database is required to be updated quarterly, or more often if the status of the trial changes.

G. NIAMS Review of the Application

In the initial peer review by NIAMS, applicants may be invited to participate in an applicant interview, i.e., meet with the committee or be contacted by telephone. This initial peer review is concerned with scientific, technical, and management issues. For initial review of the overall clinical trial application, the review criteria will include: SIGNIFICANCE; APPROACH; INNOVATION; INVESTIGATOR; ENVIRONMENT; AND OVERALL EVALUATION. The following sections provide typical issues/items that reviewers are asked to address in the evaluation of clinical trial applications.

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 this study on the concepts or methods that drive this field? Evaluate the impact of the proposed study on the scientific and/or medical community, and the appropriateness of the aims. Evaluate the importance of the study in terms of its cost and benefit.

Approach: Are the conceptual framework, design (including composition of study population), methods, and analyses adequately developed, well-integrated, and appropriate to the aims of the study? Does the applicant acknowledge potential problem areas and consider alternative tactics?

Critique the proposed methods and detail their strengths and weaknesses. Attention should be given to the following items: Study Overview/Design; Study Population (Inclusion/Exclusion Criteria); Recruitment and Retention; Randomization; Study Procedures (Interventions/Treatments); Clinical Management (Administration of Drug/Monitoring); Compliance Issues; Study Outcomes; Adverse Events; Study Difficulties/Limitations; Core Lab(s) Activities (if applicable); Economic Analysis (if applicable); Quality of Life Assessment (if applicable); Ancillary Studies (if applicable); Timeline; Statistical Analysis (Techniques/Methods); Power Analysis and Sample Size; Certification and Training; Data Collection/Processing; Data Management (Monitoring/Safety/Quality Assurance/Confidentiality).

Innovation: Are the aims original and/or innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? Evaluate what is known about the subject under investigation and whether the scientific base is sufficiently well developed to justify the proposed study. Include reference to both basic and clinical aspects of the research as well as previous relevant pilot and fully controlled studies by the applicant.

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)? Evaluate the expertise and responsibilities of the key staff members. Responsibilities should be appropriate, as well as realistic, in light of other ongoing research commitments by the staff members. Do not include descriptive biographical information, unless important to the evaluation of merit. Do not discuss investigators in the clinical centers individually unless they are outliers (exceptionally good or of questionable adequacy); otherwise, a general statement about the clinical centers is appropriate.

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? Critique the facilities and resources available to the study. For multicenter applications, critique the ability of individual centers to: 1) enroll the proposed numbers, 2) adhere to the protocol, 3) collect and transmit data in an accurate and timely fashion, and 4) operate within the proposed organizational structure. Do not describe the clinical centers individually except to note inadequacies; otherwise, a general statement about the clinical centers is appropriate.

Overall Evaluation: In one paragraph, the reviewer should briefly summarize the strengths and weaknesses of the application, and recommend a score reflecting the overall impact of the proposed research on the field, weighing the above criteria as felt to be appropriate for this application.

Inclusion of Women, Minorities, and Children: The NIH has adopted the 1997 Office of Management and Budget (OMB) revised minimum standards for maintaining, collecting, and presenting data on race and ethnicity for all grant applications, contract and intramural proposals and for all active research grants, cooperative agreements, contract and intramural projects. The following document NIH Policy on Reporting Race and Ethnicity Data: Subjects in Clinical Research http://grants.nih.gov/grants/guide/notice-files/NOT-OD-01-053.html (released on August 8, 2001) provides the detailed description of these policies.

These issues will be evaluated and may impact on the scientific evaluation of the overall application and individual clinical sites.

The reviewers will evaluate whether plans for recruitment/retention of women, minorities, and children are adequately addressed regarding the scientific basis for the study. Exclusion or inadequate representation of women, minorities, and children must be justified. Exclusion of children or a restricted age range must also be justified. Scientific, ethical, and other factors may influence recruitment plans. If there is inadequate representation, missing, or incomplete recruitment/retention plans, the reason should be clearly stated. The percent representation expected for each group should be included.

The appropriateness of the following issues will also be assessed, but normally do not have an impact on the scientific evaluation:

Budget: All reviewers are asked to make recommendations about the appropriateness of the budget, whether or not each component has been adequately justified, and appropriateness of the budget items (Personnel, Consultants, Equipment, Supplies, Travel, Other) in relation to the importance of work proposed.

Human Subjects: Evaluate the treatment of human subjects. Examine the risk/benefits to subjects and indicate whether or not: 1) they will be at risk; 2) the informed consent forms are provided and are adequate for the proposed study; 3) procedures have been included to deal with potential untoward effects; and 4) measures have been taken to protect the anonymity of subjects.

Data Safety and Monitoring: Beginning with the October 2000 receipt date, investigators must submit a monitoring plan for all clinical trials to the funding Institute and Center (IC) as part of the research application. This plan will be reviewed by the scientific review group and any comments and concerns will be included in an administrative note in the summary statement. At a minimum, monitoring plans must include a general description of the reporting mechanisms for adverse events to the IRB(s), FDA, and the NIH.

The following documents NIH Policy for Data and Safety Monitoring http://grants.nih.gov/grants/guide/notice-files/not98-084.html (released on June 10, 1998) and Further Guidance on Data and Safety Monitoring for Phase I and Phase II Trials http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html (released on June 5, 2000) provide the detailed description of these policies.

NIAMS Second Level of Review

All applications undergo a second level of review by the NIAMS Advisory Council prior to award. The purpose of this review is to consider the trial in the context of the overall plans and activities of NIAMS. Council recommendations reflect such factors as programmatic priority, balance, and the benefit of the trial.

H. Submission of Application

Receipt dates for all investigator-initiated clinical trial grant applications are as follows:

February 1
June 1
October 1

Applications in the modular format are not acceptable.

The National Institutes of Health's Center for Scientific Review (CSR) has the responsibility for assigning applications to the appropriate institute. An assignment to NIAMS will be based on the goals of the proposed program.

Submit a signed, typewritten original of the application, including the Checklist, and five signed, exact, clear, single-sided photocopies of the completed application 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).