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NINDS Terms of Award for Phase III and Other Large Clinical Trials, and Large Epidemiological Studies

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  1. The NINDS has a responsibility to ensure that mechanisms and procedures are in place to protect the safety of participants in NINDS-supported clinical trials. Therefore, prior to subject accrual, the Awardee will provide the following for review and approval by the NINDS:
    • The detailed plan for data and safety monitoring (see Section B below)
    • The clinical research protocol, including details of study design, proposed interventions, patient eligibility and exclusion criteria, plans for the management of side effects, procedures for assessing and reporting adverse events, and data analysis plans. Refer to the protocol template.
    • Written responses to the concerns and suggestions raised by the NIH study section in the summary statement of the application.
    • The plans for ensuring data quality, e.g. through site monitoring (i.e., verifying study data through comparison to source documents, pharmacy audit, etc.). Refer to the data quality document.
    • If the Recombinant DNA Advisory Committee (RAC) or the Secretary's Advisory Committee for Xenotransplantation (SACX) has reviewed the clinical protocol, the Awardee should provide information about the review and approval.
    • Clinical research projects involving the testing of new investigational therapeutics, new indications for FDA-approved drugs, vaccines, devices or other medical interventions under a research protocol should be performed under an IND/IDE, unless otherwise agreed upon by the US FDA. If the proposed clinical trial will be done under an existing IND/IDE, the Awardee must provide the NINDS with the name and organization of the IND/IDE holder, the date the IND/IDE was filed with the FDA, the FDA IND/IDE number, and any comments from the FDA regarding this protocol. In addition, a copy of the FDA Form 1572 for each participating site must be provided to the Awardee.
    • In studies where a pharmaceutical/biotechnology company is providing the study agent/device, a written agreement by a company official affirming this arrangement.

    Within 30 days of receipt of all of these documents, NINDS staff will review the study documentation and inform the Awardee in writing of any remaining issues that need to be resolved. In some cases, the NINDS will send a team of site visitors to the PI's site to help ensure that the study is ready to proceed.

  2. Data and Safety Monitoring Requirements

    Independent monitoring of interim data is strongly recommended for all clinical trials. A final data monitoring plan must be agreed upon by the Awardee and the NINDS before study enrollment commences. For further information, refer to the NINDS Guidelines for Data and Safety Monitoring in Clinical Trials.
  3. Futility Analyses

    In addition, all major clinical trials, i.e. phase III trials or trials costing more than $1 million/year, are required to include plans for futility analyses. Because major clinical trials consume significant resources of the NINDS, and because it may be unethical to keep study subjects involved in a trial if it is unlikely to come to a definitive conclusion, the NINDS requires the study investigators to incorporate into their analysis plan two types of futility analyses. First, the analysis plan must include periodic evaluations of the likelihood of successfully completing study accrual on time. Before the study opens to accrual, the investigators should specify both the target and minimally acceptable accrual goals for the study. The goals must be approved by the DSMB. The DSMB should continually monitor study accrual and give serious consideration to terminating the study if it fails to meet the minimally acceptable goals. Second, the analysis plan must include at least one evaluation of the likelihood (e.g. conditional power) of the study being able to reach a firm conclusion regarding the primary outcome of the trial. The only exceptions to this requirement are if the investigators can convince the DSMB that the trial (1) is worth continuing to completion to observe important secondary outcomes or (2) is designed in such a way that early termination for futility would not result in significant savings of either funding or subject risks/inconveniences.
  4. Changes in Protocol Design and Status

    To help ensure the safety of subjects enrolled in NINDS -funded studies, the Awardee must provide the NINDS with copies of documents related to all major changes in the status of ongoing protocols, including:
    • Amendments to the protocol
    • Termination of the protocol
    • Temporary suspension of the protocol
    • Changes in informed consent or IRB/EC approval status
    • Temporary suspension or permanent termination of patient accrual
    • Other problems or issues that could affect the human subjects in the studies

    Notification of any of the above changes must be made within three (3) working days by e-mail, followed by a letter from the Principal Investigator, detailing the change of status notification to the local IRB/EC and a copy of any responses from the IRB/EC. Changes should not be implemented without written approval of the NINDS program official.

  5. Funding

    Funding support recommended for each year of the project is only an estimate and is contingent upon favorable review by NINDS staff of the progress of the project, sufficient subject accrual, and demonstrated need for the funds. Funds awarded for patient care costs may not be used for any other purpose without the prior written approval of the NINDS.

    Personnel funds must be managed in a way that allocates personnel effort and salary charges in accordance with the work being carried out in this project. Specifically, if accrual is delayed or lags, or if the needs of the project do not require full personnel effort and salaries as awarded, proportionate reductions in effort and salary charges will be instituted as needed both at the parent grant site and at participating sites. NINDS personnel will provide guidance as needed for determining appropriate personnel charges, given the work scope at any particular time.

    NINDS staff will work with the Principal Investigators [or Steering Committee or Clinical Coordinating Center] to devise a plan to assess the performance of each clinical site with respect to recruitment and retention of participants, data quality and completeness, compliance with human subjects concerns, and other considerations. This assessment will be used to redistribute site funding so as to maximize the likelihood of successful study completion. In some cases, a site may be closed to further recruitment and may be funded only to complete follow-up of current study participants. Refer to our  incremental funding guidelines.

  6. Other Required Reporting During the Award Period

    Awardees are required to notify the NINDS of any of the following circumstances:
    • Plans to add or discontinue institutions in a multicenter study. The NINDS must receive a justification from the Awardee at least thirty (30) days in advance of making such a change, and must concur with the decision.
    • A change in the Principal Investigator at a site. The CV of the new Principal Investigator must be submitted to the NINDS thirty (30) days in advance of the anticipated change. Documentation that the new Principal Investigator has completed NIH-required training in human subjects protection should also be provided.
    • A change in the membership or operating procedures of the Study Monitoring Committee (SMC) or a change of the Independent Medical Monitor. The CV of the new SMC member or Monitor must be submitted to the NINDS thirty (30) days in advance of the anticipated change.
    • Any significant correspondence from the FDA concerning the trial. This applies to clinical trials funded in whole or in part by the NINDS and involving an IND/IDE (regardless of who the official sponsor is). Such correspondence includes warning letters, investigator disqualification notices, clinical holds, etc. This correspondence from the FDA must be submitted to the NINDS within 72 hours of the Awardee learning of it. For further details, consult the NIH policy.
    • Any significant correspondence from the IRB concerning the study regarding human subjects and protocol approval/disapproval or suspension must be submitted to the NINDS within 72 hours of the Awardee learning of it.
  7. Study Close-out

    A study close-out plan should be formulated by the investigators to unblind and debrief site staff and study participants upon trial completion. Information on close-out procedures can be found in our Manual of Procedures (MOP) template. The study close-out plan should be reviewed and approved by the safety monitoring group (IMM, SMC or DSMB) for the trial.
  8. Gender and Minority Data Analyses

    A description of plans to conduct analyses, as appropriate, by sex/gender and/or racial/ethnic groups must be included in Phase III clinical trial protocols. Cumulative subject accrual and progress in conducting subset analyses must be reported to NIH in the annual Progress Reports. Final analyses of sex/gender and racial/ethnic differences must be reported in the required Final Progress Report or Competitive Renewal Applications, as stated in Section IIB of the NIH Guidelines on the Inclusion of Women and Minorities as Subjects in Clinical Research.
  9. Publication of Data and Analyses

    Timely publication of major findings is essential. Specifically, the primary study results should be submitted for publication in a peer-reviewed journal within one year of completion of the follow-up of subjects in the clinical trial. Any papers published under the auspices of this award must cite the funding support of all pertinent NIH Institutes.
  10. Archiving of Data

    Because of the extensive effort of investigators to collect, verify and analyze the data for clinical trials, it is expected that appropriate procedures and methods will be established for archiving the data for access within one year following publication of the primary study results. See the NIH guidelines on sharing research data.
  11. Special terms and conditions for multicenter Phase III clinical trials

    In addition to the items discussed under section B, the NINDS must receive and approve a final study manual of operations before subject enrollment may begin.

    • Conversion of Funding Mechanism From R01 to Cooperative Agreement (U01/U10) Mechanism

      Grants (R01) supporting major clinical trials (e.g. phase III clinical trial, multicenter trials, or costing more than $1 million/year) and large epidemiological studies may be converted to cooperative agreements. Refer to the U01 Notice at: http://grants.nih.gov/grants/guide/notice-files/NOT-NS-05-003.html
    • Steering Committee

      The Principal Investigator, in consultation with the NINDS Program Director, will establish a Steering Committee as the main governing body of the study that will include the NINDS Program Director (or his/her designee) as a voting member. The Steering Committee will be responsible for providing study oversight by monitoring safety procedures and on-site data quality, and evaluating the progress of the project using performance measures such as patient accrual/retention, data quality and scientific contributions. The Steering Committee will carry out these responsibilities with the assistance of various study subcommittees, e.g. recruitment/retention, conflict of interest (add link to COI policy), and publication; the NINDS Program Official will serve on subcommittees as he/she deems appropriate.
    • Reporting

      Information regarding the number of participants randomized to the study, the completeness of follow-up, and other data necessary to assess research progress and to plan expenditure of funds shall be sent to NINDS (attn: Program Director) summarizing progress, including data on subject accrual, completeness of data, and participant safety. The first report will be due 120 days after the notice of grant award has been issued, reflecting the first 90 days of the grant period. Subsequent reports should be sent to the NINDS Program Director (or the Administrative Program Official for U01's) at 90 day intervals (or other mutually agreed upon schedule). All attempts will be made to have this quarterly report  (PDF file) coincide with reporting to the DSMB or other oversight committee reports (whenever possible).

For additional information on study documentation needed for NINDS -supported clinical trials, refer to the Clinical Trials Checklist [MS Word Version] [PDF Version]

 

Last updated August 14, 2008