Possible Terms and Conditions for NIDCD Clinical Trials Supported as Cooperative Agreements

The following special terms of award are in addition to, and not in lieu of, otherwise applicable OMB administrative guidelines, HHS grant administrative regulations at 45 CFR Parts 74 and 92 (Part 92 is applicable when State and local Government are eligible to apply), and other HHS, PHS, and NIH grant administration policies.

These terms and conditions of award are representative of the specific terms and conditions that will be negotiated with the applicant prior to award. The terms and conditions will be modified as appropriate to each clinical trial, consistent with the complexity of the preliminary clinical trial.

The administrative and funding instruments used for this program will be a cooperative agreement (U01), an “assistance” mechanism (rather than an “acquisition” mechanism), in which substantial NIH programmatic involvement with the awardees is anticipated during the performance of the activities. Under the cooperative agreement, the NIH’s purpose is to support and stimulate the recipients’ activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with the concept, the dominant role and prime responsibility resides with the awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined below.

Principal Investigator (Awardee) Rights and Responsibilities

A. The Principal Investigator (PI) will have primary responsibility for all aspects of his or her study, including any modification of study design, conduct of the study, quality control, data analysis and interpretation, preparation of publications, dissemination of data, tools and technologies, and collaboration with other investigators. The awardees agree to accept close coordination, cooperation, and participation of NIDCD staff in those aspects of scientific and technical management of the study as stated in these terms and conditions.

B. The PI will have primary responsibility to conform to NIDCD policy regarding the monitoring of studies commensurate with the degree of potential risk to study participants and the complexity of the study. The NIDCD Data and Safety Monitoring Guidelines that investigators should use in establishing the appropriate data and safety monitoring for their research study can be found here.

C. The clinical trial protocol will be subject to review and acceptance (in an advisory capacity only) by the Data and Safety Monitoring Board (DSMB). Upon implementation of the protocol, each study site, whether a single institution or consortium of institutions, will follow the procedures required by the protocol regarding study conduct and monitoring, participant safety and management, data collection, and quality control.

D. The nature of the clinical trial (e.g., single-site vs. multi-site, simple vs. complex, high-risk vs. low-risk) will determine if a governing committee is necessary. It is expected that most multi-site or high-risk trials should have a primary governing committee (such as a Steering Committee), whose primary functions are to oversee scientific and policy issues such as protocol amendments, publications policy, and ancillary studies. Voting membership on this committee shall consist of the PI, Director of the Data Coordinating Center, and other key investigators. Meetings of the Steering Committee will be held as needed, but no less than once a year.

E. The PI will be responsible, through a Data Coordinating Center (DCC), for ensuring the provision of centralized data management and coordination assistance. The DCC is responsible for providing all data coordination and management, including quality control and analysis, using procedures and standards determined by the DCC. The DCC will provide technical assistance and data management services to the study sites with respect to quality control, uniformity of data collection, management of the collective database, and data analysis and publication. The DCC will be responsible for the acquisition and distribution of study materials involved in the protocol. The DCC will also arrange for the appropriate approvals (when necessary) from the Food and Drug Administration (FDA) with respect to the use of investigational drugs, biologics, or devices. Any post-award changes in the selection of the facility or organization serving as the DCC will require NIDCD approval.

F. A change in PI (who may serve as the Study Chair), in any of the key personnel identified in the Notice of Grant Award, or in the facility serving as the DCC must have prior written approval of the NIDCD Grants Management Specialist in consultation with the NIDCD Project Coordinator.

G. Awardee(s) will retain custody of and have primary rights to his or her data developed under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies.

H. Support or other involvement of industry or another third party in the study may be advantageous and appropriate. However, except for licensing of patents or copyrights, support or involvement of any third party will occur only following notification of and concurrence by NIDCD.

I. The awardee(s) are expected to put all study materials and procedure manuals into the public domain. Awardees are expected to publish and publicly disseminate results, data, and other products of the study, concordant with governance policies and protocols. Review and approval by the appropriate governing committee will be required for all analyses prior to publication or presentation according to policies developed by the governing committee. Study sites wishing to perform analysis of local data must also obtain the consent of the NIDCD Project Coordinator for any such analyses prior to initiation. During the project period and within three years beyond the end date of the project period of NIDCD support, unpublished data, unpublished results, data sets not previously released, or other study materials or products are to be made available to any third party only with the approval of the governing committee. Any web site developed for dissemination of information may be linked to the NIDCD web site. Publications and oral presentations of work performed under this agreement will require appropriate acknowledgement of support by the NIDCD/NIH.

NIDCD Responsibilities

A. An NIDCD Project Coordinator will be responsible for normal stewardship of the award, as named in the notice of grant award. This Project Coordinator will have substantial programmatic involvement during the conduct of this activity through technical assistance, advice, and coordination above and beyond normal program stewardship for grants, as detailed below.

Note: The NIDCD Project Coordinator will serve as the initial contact for the PI prior to grant application submission. However, advice regarding the study protocol will not take place till AFTER peer review. If the grant application is selected for funding, the NIDCD Project Coordinator may provide input to finalize the development of the protocol and to bring the final protocol to the DSMB for final approval prior to trial implementation.

B. The NIDCD Project Coordinator will serve as a non-voting member, and attend all teleconference meetings of the appropriate governing committees (such as the Steering Committee); he or she may serve on other study committees when appropriate. The NIDCD Project Coordinator may work with awardees on issues coming before the governing committees and other committees as appropriate, e.g., study monitoring, bioinformatics, final data analysis and interpretation, technology dissemination, and preparation of publications. The NIDCD Project Coordinator will serve as a resource to the governing committee in the development of solutions to major problems as they arise, and provide an oversight perspective of study conduct and performance.

C. The NIDCD Project Coordinator will oversee the monitoring of study progress and the performance of each participating site through communications with the PI, participation on study calls, and review of periodic or annual study monitoring and progress reports, as appropriate. This review may include, but is not limited to, compliance with the study protocol, meeting patient enrollment targets, adherence to uniform data collection procedures, and the timeliness and quality of data reporting. The Project Coordinator may conduct site visits, as necessary. As with any award, continuation, even during the period recommended for support, is conditional upon satisfactory progress. The NIDCD retains the option of exercising periodic external peer review of progress.

D. The study should name its own medical monitor (for the entire study if a multi-site trial), who will have the primary responsibility for immediate oversight of participant safety. In the event of emerging safety issues or discrepant safety assessments, the NIDCD Project Coordinator will bring the issue or case to the attention of the DSMB Chair either immediately or in the course of a DSMB review.

E. A Data and Safety Monitoring Board (DSMB) will be appointed by NIDCD to provide independent recommendations regarding the continuation, modification, or termination of the trial based on ethical concerns or observed beneficial or adverse effects of any of the interventions under study. The DSMB members and chair will be selected by NIDCD.

F. The NIDCD reserves the right to terminate or curtail the study (or an individual award) in the event of

• Failure to develop or implement a mutually agreeable collaboration protocol;
• A substantial shortfall in participant recruitment, follow-up, data reporting and dissemination, quality control, or other major breach of the protocol;
• Substantial changes in the agreed-upon protocol with which NIDCD does not concur;
• Reaching a major study endpoint substantially before schedule with persuasive statistical evidence; or
• Human subject ethical issues that may dictate a premature termination.

G. The NIDCD Project Coordinator, on behalf of the NIDCD, will have the same access, privileges, and responsibilities regarding the collaborative data as the other members of the cooperative agreement awardees. The Government, through the NIDCD Project Coordinator, will have access to data generated under this cooperative agreement at the end of the clinical trial.

Collaborative Responsibilities

As appropriate to the funded clinical trial, the following collaborative responsibilities will be incorporated in the grant award.

A. Primary Governing Committee (or Steering Committee): This Committee will assume a primary governing role in the study. The PI will chair the Committee, which includes other members of the study leadership, the NIDCD Project Coordinator, the Director of the Data Coordinating Center, and a subset of the Site Investigators from the participating clinical sites. Committee membership should possess expertise in all the disciplines necessary for carrying out the proposed protocol and conducting the proposed research. The NIDCD Project Coordinator is a non-voting member.

The Steering Committee (SC) is responsible for overseeing all aspects of the multi-site clinical trial, including implementation of the study protocol, oversight of recruitment retention and enrollment, review of reports from other trial committees, and preparing and publishing scientific reports. Awardees will be required to accept and implement the common protocol and procedures approved by the SC. Meetings of the primary governing committee will be held as needed, but not less than once a year, including face-to-face meetings if necessary.

B. Data and Safety Monitoring Board (DSMB): An independent DSMB will be appointed by NIDCD for the purpose of monitoring the conduct of the clinical trial. The PI, in conjunction with staff of the Data Coordinating Center, will provide any data requested by the DSMB for review. The DSMB will review progress at least annually (more often if necessary), and report to NIDCD. The DSMB will meet via teleconference or in person to:

• Review the research protocol and plan for data and safety monitoring;
• Evaluate the progress of the trial, including periodic assessments of data quality and timeliness, participant recruitment, accrual and retention, and participant risk/benefit changes;
• Oversee adherence to the protocol and maintenance of data confidentiality;
• Review safety data, including adverse events and reportable events; and
• Make recommendations regarding the continuation or conclusion of the study.

The DSMB monitoring function is above and beyond that traditionally provided by the institutional review boards (IRBs); however, the IRB must be cognizant of the procedures used by DSMBs. The DSMBs will provide periodic reports to investigators for transmittal to the local IRBs. The Grantee Institution and PI are responsible for ensuring that Clinical Sites follow approved protocols and maintain quality control of data in accordance with the DSMB guidance and recommendations. Proposed protocol changes must be approved by the DSMB. Any major problems concerning the compliance of study sites in the protocol or quality control of data should be reported immediately by the PI to the NIDCD Project Coordinator.

C. The addition or deletion of study sites is a prior approval authority retained by the awarding office; therefore, all changes in study sites must be approved in writing by NIDCD. For additional sites, the awardee should provide NIDCD with countersigned documentation of agreements between the two parties, proposed budget, justification for addition, and the appropriate human assurances. Requests for deletion of sites should be accompanied by a justification and budgetary changes.

Arbitration Process

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to arbitration. An Arbitration Panel composed of three members will be convened. It will have three members: a member chosen by the Steering Committee (without NIDCD staff voting), a member chosen by NIDCD, and a third member with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual awardee. This special arbitration procedure in no way affects the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulations 42 CFR Part 50, Subpart D and HHS regulations 45 CFR Part 16.

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