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

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 .
   • Study Manual of Procedures
   • 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 in the United States 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 not exempt, 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 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.  Monitoring plans may include oversight by a NINDS Data and Safety Monitoring Board (DSMB), a non-NINDS Safety Monitoring Committee (SMC) or Independent Medical Monitoring.  If the monitoring plan includes NINDS Data Safety and Monitoring Board (DBMB) oversight, the NINDS’ approval of the DSMB’s recommendation to start the trial should be provided to the Awardee prior to subject accrual .  Any exceptions should be approved by the Director of the Office of Clinical Research. For further information, refer to the NINDS Guidelines for Data and Safety Monitoring in Clinical Trials .
   
3. Use of NINDS Common Data Elements (CDEs)
   
   The NINDS strongly encourages researchers who receive funding from the Institute to use the NINDS Common Data Elements (CDEs) available at www.commondataelements.ninds.nih.gov or document how they will ensure their data collection is compatible with the CDEs.  Investigators should use the common definitions and the standardized case report forms and other instruments indentified by the CDE Project.  The CDE Project has developed uniform formats by which clinical data can be systematically collected, analyzed and shared across the research community.
   
   The NINDS Program Official must approve awardees plan for using CDEs before enrolling the first study participant.  Justification must be clearly provided in the plan if any general CDE or disease-specific (as available) will not be used.

4. Futility Assessments
   
   All major clinical trials, i.e. phase III trials or trials costing more than $1 million/year, are required to include plans for futility assessments.  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 assessments.
   
   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.  There may be exceptions to this requirement if 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.

5. 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.

6. 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 both at the parent grant site and at participating sites.  NINDS personnel will provide guidance for determining appropriate personnel charges and levels of effort.
   
   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 may 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.

7. Clinicaltrials.gov Registration and Results Reporting
   
   ClinicalTrials.gov is a database of federally and privately supported research trials to test the effect of treatments and procedures for a wide range of diseases and conditions.  The NIH is committed to providing information to increase public awareness and access to clinical trials sponsored federally and by industry and foundations.  Awardee is required to comply with Public Law 110-85 (Food and Drug Amendments Act of 2007: FDAAA), as applicable, for required clinical trial registration and results reporting.
   
   NIH encourages registration of all trials whether required under the law or not.  For more information see the NIH Office of Extramural Research website, "What NIH Grantees Need to Know about ClinicalTrials.gov and FDAAA."
   
   This award provides support for one or more clinical trials.  NINDS is not the sponsor of any applicable clinical trial conducted under this award.
   
   By law (Title VIII, Section 801 of Public Law 110-85), the “responsible party” must register Phase II-IV “applicable clinical trials” on the Clinicaltrials.gov Protocol Registration System (PRS) Information Web site.  Applicable clinical trials must be registered no later than 21 days after the first participant is enrolled.  "Basic results" information for applicable clinical trials is to be submitted within one year after the “Primary Completion Date” of the trial.
   
   Awardee must certify compliance with FDAAA in continuation progress report.  Instructions on compliance certification are available on the NIH website.

8. 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 any external advisory committees, including Safety Monitoring Committee (SMC), or a change of the Medical Monitor.  The CV of any new Study Monitoring Committee (SMC) member or Medical 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 receiving it.
     
9. Study Close-out
   
   A study close-out plan should be formulated by the investigators to unmask and debrief site staff and study participants upon trial completion.  Information on close-out procedures can be found in the 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.
   
10. Gender and Minority Data Analyses
    
    Since a primary aim of research is to provide scientific evidence leading to a change in health policy or standard of care, it is imperative to determine whether the intervention or therapy being studied affects women or men or members of minority groups and their subpopulations differently.  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 .

11. 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.  In accordance with PL. 110-161, compliance with the NIH Public Access Policy is mandatory.  For more information, see NOT-OD-08-033 and the Public Access website .
    
12.  Data Sharing
    
    Because of the extensive effort that went into collecting data by investigators and study participants, it is important that datasets from completed studies be available for further research so that the full potential of the datasets is maximized.  It is expected that investigators submit to NINDS Office of Clinical Research a cleaned dataset and any supporting documentation (meta information) required for the analysis of the data within one year of the primary publication or within two years of the last study visit of the last subject.  See the NIH guidelines on sharing research data .
    
13. Special terms and conditions for multicenter Phase III clinical trials
    
    • 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 Project Scientist 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, and publication; the NINDS Program Official will serve on subcommittees as he/she deems appropriate.
      
    • Reporting
      
      To assess research progress, enrollment reports shall be sent to the NINDS (attn: Program Director) three times annually summarizing data on subject accrual (overall and by site), date of first randomization and participant retention.  Study progress will be reported to the NINDS National Advisory Council.
    • Financial Status
      
      The PI is expected to be aware of the financial status of their grant and should inform NINDS of any concerns.  Awardee must submit an estimate of funds expended and funds remaining to the program director annually.  This does not replace the FSR submitted by the Institution on a yearly basis to the NINDS GMO, but serves to help the NINDS Program Officer and the Steering Committee gage expenditures relative to study progress

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

See All NINDS Terms of Award for Clinical Research