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National Center for Complementary and Integrative Health

NCCIH Policy: Applications for Large Budget Clinical Trials Over $500,000 in Direct Costs in Any Year

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A. Purpose

This document describes the National Center for Complementary and Integrative Health (NCCIH) policy requiring documented approval from NCCIH before investigator-initiated large budget clinical trial applications can be submitted.

B. Scope

This policy applies specifically to investigator-initiated new, renewal (competing continuation), resubmission (amended), or revision (competing supplement) clinical trial applications requesting $500,000 or more in direct costs in any one year. First-tier consortium or contractual facilities and administrative (F&A) costs do not count against the direct cost threshold. For companion clinical and data coordinating center applications for multisite trials, the combined budgets of the clinical coordinating center (CCC) and data coordinating center (DCC) will be used to determine if this threshold is met.

Prospective applicants should refer to Section IV (Application and Submission Information) of the FOA the investigator is using for the clinical trial application. This document describes the procedure required for researchers to request NCCIH’s permission to apply.

C. Process

To obtain NCCIH permission to submit a large budget clinical trial application, a potential applicant must:

  • Discuss the proposed research project with NCCIH program staff 3−6 months prior to the planned application receipt date
  • Submit a letter requesting permission to apply to NCCIH at least 6 weeks prior to the planned application receipt date.

Contact Program Staff

This communication is the first step in requesting approval to submit a large budget clinical trial application. It is a discussion between an NCCIH program director and the principal investigator (PI) and key personnel of a proposed research project. To adequately prepare for this discussion, the PI should provide the relevant NCCIH program director with a two- to three-page summary of the concept for the clinical trial. This communication with NCCIH staff: (1) ensures NCCIH receives applications that are scientifically aligned with NCCIH’s mission and strategic vision; (2) assists investigators with finding the best funding opportunity for the stage of research the investigator proposes to conduct; and (3) enables NCCIH to consider the budgetary impact of supporting the project.

Letter of Request for Permission To Apply

The prospective applicant(s) will be notified via email if they are being invited to submit a letter of request for permission to apply (RPA). The RPA serves as the formal request from the PI seeking permission to submit a large budget clinical trial application. In the event NCCIH determines the proposed application does not fit with the goals and objectives of the NCCIH clinical research portfolio, the PI will be provided feedback as to why the proposal was not a good fit and what other options are available to support the proposed work. For NCCIH to make an informed decision about whether permission will be given to apply, the RPA should be approximately 10 pages in length and include or address the following:

  1. Title of the proposed project.
  2. Anticipated application receipt date.
  3. Key personnel (the eRA Commons user ID for the PI or contact PI) for both the clinical and data coordinating center applications.
  4. Primary institution for the application and any additional institutions involved in the linked set of applications.
  5. Total years of support requested* (planning and implementation phases), estimated direct costs, contract F&A costs, and total costs for each year of the proposed project. A brief budget justification should be included—to also contain the per patient costs for the trial and sample size.
  6. Brief description of the scientific rationale for the study.
  7. Statement of the compelling public health need and the study’s potential impact on health care, including relevance to addressing gaps in research evidence or health care guidelines.
  8. Description of the specific aims of the proposed project, including any subprojects or secondary aims. Provide hypotheses that will be tested and outcomes that will be measured.
  9. Description of the study design and explanation of how the design will fulfill the intent of the study. Include a flow diagram of the study if appropriate.
  10. Plans for resource sharing, including data and samples where appropriate.
  11. References.

*Proposed third-party support: A letter notifying NCCIH about any proposed third-party support, the estimated commitment level, and possible contingency plans in the event that the third-party support is terminated during the research project should be submitted by the PI at the same time as the letter of request. This letter is nonbinding and is for planning purposes only. If NCCIH decides to fund the application, prior to the Notice of Award NCCIH will request that the grant applicant’s Authorized Organization Representative (AOR) submit a formal Third-Party Contribution Agreement signed by the third party’s AOR. In addition, NCCIH funding of an application with third-party support may be contingent on securing cofunding from those sources.

The following is additional information that may be informative to include in your request for permission to apply, particularly if you are proposing a multisite efficacy, effectiveness, or pragmatic trial. If granted permission to apply, the investigator should consider this type of information when formulating the full application.

  1. Describe the statistical assumptions made to estimate the needed sample size. Provide enough detail so another statistician could replicate your power calculations.
  2. Concisely describe prior studies that directly support feasibility of the planned study and efficacy/effectiveness of the intervention for the condition in the target population.
  3. Within the description of the study design, provide these details:
    • Define the primary and secondary outcomes and how they will be measured.
    • Define the patient population that will be enrolled.
    • Describe the intervention condition and what the comparison condition will be. If applicable, describe how the intervention will be administered including frequency and duration of treatment, and how fidelity to the intervention will be assessed.
  4. Provide a summary of the analytic plan, including the general statistical assumptions for the proposed study design and analysis. Specify whether an intention to treat analysis will be performed. Explain how missing data, outliers, noncompliance, and losses to followup will be handled in the analysis. If appropriate, specify the study stopping rules for efficacy, futility, or poor study performance.
  5. Describe the method for identifying and recruiting participants. Describe potential collaborating sites, including the demographics and availability of the study population at those sites. List specific inclusion and exclusion criteria. Address how these criteria may affect participant recruitment and retention.
  6. Provide a summary of safety/risk issues and how they will be monitored and addressed.
  7. Provide a proposed start date, duration, and timeline of the clinical trial. Include time for study startup, closeout, data cleaning, and data analysis.
  8. Describe the extent and type of blinding/masking. If possible, persons measuring the primary outcome should be masked.
  9. Include identification and a brief description of the roles and responsibilities the DCC will accomplish for the study.

Criteria for NCCIH’s Decision

NCCIH considers the following criteria in determining whether to give permission to apply:

  • Relevance to NCCIH: Importance of the clinical trial impact to the NCCIH mission and strategic plan. Will the proposed research significantly advance the mission of NCCIH?
  • Programmatic priority: Is the proposed clinical trial in an area that has been determined to be a high priority for NCCIH?
  • Programmatic balance: How does the proposed clinical trial relate to currently funded research by NCCIH, other funded trials (clinicaltrials.gov), and the investigative team?
  • Potential impact: Will the proposed clinical trial significantly advance the field? Will the results have an impact on clinical practice, guidelines, or health care policy?
  • Budget: Are the proposed annual costs reasonable? Are there options for cost sharing with other Federal and non-Federal entities? Are other NIH institutes or centers (ICs) interested in cofunding?
  • Is there a strong scientific rationale for the design of the clinical trial? Does the preliminary data justify the proposed clinical trial?
  • Is the proposed clinical trial feasible and likely to be achieved with the proposed sites of the CCC and the data management of the DCC?

Notification of NCCIH’s Decision

Within 3 to 4 weeks of receipt of the letter of request, NCCIH will notify the applicant in writing about its decision (or request additional information on the proposed application). If NCCIH has given permission to submit the application, the PI will receive a letter indicating this, as well as the maximum budget that will be allowed in the application.

Please note: Giving permission to submit an application does not guarantee that NCCIH will fund the application or that it will fund the application at the requested levels, regardless of the outcome of peer review.

Submitting the Application

To facilitate receipt of the application, applicants must include a cover letter with the application that identifies the NCCIH program staff member(s) with whom they have been in contact regarding the application. The second page of the cover letter should be the documentation from NCCIH granting permission to submit the large budget clinical trial application. If the subtotal direct cost on the cover page of the application exceeds the amount NCCIH agreed to accept, the application may be withdrawn or not awarded.

Instructions for Resubmission (Amended) Applications

NCCIH’s decision to give permission to apply for a specific receipt date automatically allows applicants to submit a single amended application (i.e., an “A1” application), provided that:

  • The submission of the A1 application occurs within 37 months of the original receipt date for the initial new (A0) application, in accordance with NOT-OD-10-140
  • The sites and subcontracts of the A1 application are the same as the original application
  • The originally proposed aims remain unchanged
  • The total direct costs per year do not exceed the amount NCCIH originally agreed to accept (excluding increases in PI salaries due to changes to the NIH salary cap).

Contingent on meeting the requirements above, an applicant intending to submit an amended (A1) application does not need to submit another letter of request. However, NCCIH requests that every applicant intending to submit an A1 application first submit a letter of intent so that NCCIH can plan for the receipt, referral, and review of the A1 application. See the “Note” below for specific instructions.

If a resubmission (A1) application does not meet all the conditions above, the applicant must initiate a new round of discussions with NCCIH staff and submit a new RPA. Changes that would require restarting the request for permission to apply process might include changes in projects or cores as well as their specific aims or their leaders.

Note: NIH policy requires documented NCCIH permission for every submission of an application with subtotal direct costs equal to or exceeding $500,000 in any one year, and NCCIH staff members need to take administrative actions so the Center for Scientific Review can accept an A1 application for peer review. Therefore, applicants must inform NCCIH staff about the intended receipt date to which they plan to submit the application. The most effective and preferred method to notify staff about the intended submission of an A1 application is through a letter of intent to the appropriate program director, with a separate copy to the Director, Office of Scientific Review, at least 6 weeks prior to submitting the application. The letter should include:

  • Receipt date and NCCIH Advisory Council round for the intended submission
  • Descriptive title of proposed research
  • Name, address, and telephone number of the PI
  • Names of other key personnel
  • Participating institutions (highlight the name of the submitting institution)
  • Number and title of the FOA to which the application is responding
  • Prior grant application number
  • eRA Commons user ID of the PI or the contact PI.

In the event the resubmission (A1) application is not awarded, applicants may submit a new (A0) large budget clinical trial application with similar science, in accordance with the NIH application submission policy as stated in NIH Guide Notice NOT-OD-14-074. However, in this circumstance, the applicant must re-initiate the process to request NCCIH permission to apply by contacting NCCIH staff. This is required even if the new (A0) large budget clinical trial application has the same science and budget as an earlier application.

D. Timing

Potential applicants are strongly encouraged to begin informal discussions with NCCIH scientific staff as early as possible in the process of planning their proposed large budget clinical trial application. Typically, this would be 3–6 months prior to the application receipt deadline. Letters of request are reviewed on a rolling basis, so it is to the investigator’s benefit to submit the letter as early in the process as possible, and thus receive a decision as to whether they are given permission to apply. This would maximize the time available to craft the actual application. At a minimum, the letter of request must be received by NCCIH at least 6 weeks prior to the application receipt date.

Application receipt dates also can be found in the specific FOA that the PI plans to use for their application. A summary of the clinical trial funding opportunities available from NCCIH is available on the “NCCIH Clinical Trial Funding Opportunity Announcements” Web site at nccih.nih.gov/grants/funding/clinicaltrials. If the deadlines in the FOA fall on a weekend or holiday, the next business day applies.

For applications to be submitted for the AIDS receipt dates, the deadlines for the presubmission milestones follow the standard schedule (i.e., the letter of request deadline is 6 weeks prior to the submission date and the deadline for completing the staff consultation is 2 months prior to the AIDS receipt date).

E. NCCIH Division of Extramural Research Director

All requests for permission to apply, subject to this policy, should be submitted (by email with the PDF document as an attachment) to the NCCIH Director of the Division of Extramural Research and copied to the relevant Branch Chief:

Emmeline Edwards, Ph.D.
Director, Division of Extramural Research
NCCIH
6707 Democracy Blvd., Suite 401
Bethesda, MD 20892-5475
Phone: 301-594-7102
Email: emmeline.edwards@nih.gov

Clinical Research Branch
Wendy Weber, N.D., Ph.D., M.P.H.
Chief, Clinical Research Branch
NCCIH
6707 Democracy Boulevard, Suite 401
Bethesda, MD 20892-5475
Phone: 301-402-1272
Email: wendy.weber@nih.gov

Basic and Mechanistic Research Branch
Wen Chen, Ph.D.
Acting Chief, Basic and Mechanistic Research Branch
NCCIH
6707 Democracy Boulevard, Suite 401
Bethesda, MD 20892-5475
Phone: 301-451-3989
Email: Wen.Chen@nih.gov

F. Frequently Asked Questions

Question 1: How are NCCIH timelines for the letter of request and (resubmission application) letter of intent affected by applications eligible for submission under the NIH policy on late submission of grant applications?

Answer: NCCIH expects applicants to adhere to the deadlines specified in this policy as they apply to the cycle for the Council to which an application is to be submitted. Given extenuating circumstances, staff members may grant latitude on these deadlines—not to exceed 2 weeks for applications submitted to standard receipt dates or 1 week for applications submitted to expedited receipt dates (e.g., AIDS receipt dates).

Question 2: How are NCCIH timelines for the letter of request and (resubmission application) letter of intent affected by applications eligible for submission under the NIH continuous submission policy?

Answer: Applications that are eligible for submission under the NIH continuous submission policy must still follow the timelines described.

G. References and Resources

Templates

(for inclusion in the required letter of request)

Policies and Guidance