Terms of Award for Phase 3 and Other Large Clinical Trials
- 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 correspondence
and comments from the FDA regarding this protocol while the IND or IDE is active.
- 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.
- 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 Study Monitoring Committee (SMC) or Independent Medical Monitoring.
If the monitoring plan includes NINDS Data and Safety 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.
- 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 identified 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 awardee's 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.
- Futility Assessments
All major clinical trials, i.e. phase 3 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, if applicable.
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.
- 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
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 [including Steering Committee or Clinical Coordinating Center as applicable]
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.
- 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
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 website. 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.
- 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.
- 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.
- 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.
- 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.
- 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 complete, cleaned, and de-identified dataset
and any supporting documentation (including but not limited to the study protocol, statistical analysis plan, and data dictionary)
required for the analysis of the data within one year of the primary publication or within 18 months of the last study visit
of the last subject, whichever occurs first. See the NIH guidelines on sharing research data.
- Special terms and conditions for multicenter Phase III clinical trials
- Steering Committee
The Principal Investigator, in consultation with the NINDS Project Scientist, 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.
The study team will submit updated enrollment information by site electronically to the NINDS Recruitment Planning and Monitoring
System (RPMS) (including startup, site activation and accrual and retention data) at least monthly during the study enrollment
- 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 FFR submitted
by the Institution on a yearly basis to the NINDS GMO, but serves to help the NINDS Program Official and the Steering Committee
gauge 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
Last updated November 17, 2014