BIPOLAR TRIALS NETWORK (BTN) PROTOCOL POLICY

 

The Bipolar Trials Network (BTN) of the National Institute of Mental Health (NIMH) is a national and international resource aimed at addressing important, timely questions of high public health significance through practical clinical trials (PCTs) in patients who suffer from bipolar disorder (BD).  The NIMH invites researchers to explore working collaboratively with the BTN in conducting PCTs in BD. Projects for the BTN are therefore expected to have major public health significance and to require the expertise and resources available on the research network.

 

The BTN comprises a network of clinics and investigative teams that the NIMH is supporting to facilitate PCTs via NIMH Contract #N01MH80001 Studies that plan to utilize the BTN infrastructure will need to obtain scientific and budgetary approval from the BTN Protocol Review Committee (BTN-PRC) and NIMH programmatic review prior to requesting funding through NIMH or other NIH Institutes.  It is anticipated that studies conducted using the BTN may be efficiently carried out in “real world” populations that have representative sociodemographic populations

 

The BTN infrastructure provides access to a rapid and cost-efficient means of recruiting and studying BD subjects, but does not include funding for any individual clinical trial, nor for the data management that a large clinical trial would require. Thus, investigators interested in conducting trials on the network must provide support for the conduct of their specific trial through NIH or NIMH grants.

 

Which Investigators are Eligible to Apply to Use the BTN?

Any investigator with an established track record of leadership of multisite clinical trials in BD is eligible to apply. In addition, individuals (with training-grant proposals) in the process of transitioning to become independent investigators who have an identified mentor with an established track record of BD research may apply.

 

What Type of Awards are Suitable for BTN Use?

Investigators interested in conducting trials with the collaborative NIH- or NIMH-supported R-01 or U-01 mechanisms may apply to use the BTN for the conduct of their specific trial. In addition, proposals involving substantive training opportunities (such as NIMH K-awards) will be considered. Research sponsored by industry or non-federal funding agencies (such as foundations) may be considered, subject to NIMH review and approval.

 

BTN Infrastructure

The BTN comprises the following: a) a core of academically affiliated bipolar specialty clinics; The Principal Investigator of each core site is a recognized leader in BD research and serves on the Executive Committee of the BTN b) a National Coordinating Center (NCC); and c) a Data Coordinating Center (DCC).   The NCC is contracted with NIMH to maintain and manage the BTN. The NCC provides scientific and organizational leadership and management of the network, overseeing protocol coordination, revising and optimizing the infrastructure, methods and procedures used as appropriate to enhance efficiency and maintaining readiness of the network and personnel to implement studies.  The DCC actively maintains and enhances current communications among all the components of the BTN, including a website, provides and maintains data collection/management and quality control systems, so they are ready for new study implementation. Applicants are required to collaborate with the BTN leadership in the development of the proposal.

BTN Goals and Objectives

The goals and objectives of the BTN are the following:

1.  To maintain an experienced multisite research network infrastructure on which to conduct studies that answer important, timely questions of high public health significance through practical clinical trials (PCTs) in patients with bipolar disorder. 

2.  To continually enhance the efficiency of the infrastructure and maintain its readiness to implement new studies.

3.  To develop new tools, methods, and designs that can enhance the usefulness and effectiveness of PCTs.

 

Clinical Research Sites of the BTN

The clinical research sites of the BTN include academic bipolar specialty clinics and experienced researchers in the bipolar field.  Site Principal Investigators are recognized nationally and internationally as scientific experts in bipolar disorder clinical trials. Final approval of any protocol using the BTN must be approved by the Executive Committee, which includes each of the site PIs.

 

BTN Protocol Review Committee (BTN-PRC)

The BTN-PRC, working with NIMH, is central in setting the scientific agenda of the BTN.  Members of the BTN-PRC include Dr. Terence Ketter (Chair), Dr. Joseph Calabrese (Co-Chair), the Principal Investigator of the BTN (Dr. Andrew Nierenberg), two additional members of the BTN Executive Committee (Drs. Charles Bowden and Michael Thase), and the Director of DCC (Deborah Wallace) and a DCC statistician. The BTN-PRC meets by telephone conference calls on a monthly basis and will meet face-to-face semi-annually, at a time and place approved by the Chair, Dr. Terence Ketter.  For meetings of the BTN-PRC, a quorum shall consist of 50% plus one of the appointed members.  Voting shall be by a simple majority As long as a quorum exists, voting may occur during the meetings, or at the discretion of the Chair, by electronic means outside meeting times. 

 

Review Process for Proposals Planning to Use the BTN

Investigators within the BTN and outside of the BTN who are interested in utilizing the BTN to conduct their own collaborative R-01/U-01, NIH- or NIMH-funded investigations among the highly generalizable BD populations in “real world” settings of the BTN, should first contact the NIMH Program Officer (Joanne Severe) to obtain a preliminary feedback on the appropriateness and feasibility of carrying out their proposal in the context of the BTN. Proposals deemed appropriate will next be referred to Drs. Terence Ketter (Chair of the BTN-PRC) or Joseph Calabrese (Co-Chair of the BTN-PRC). In addition, proposals involving substantive training opportunities (such as NIMH K-awards) will be considered. Research sponsored by industry or non-federal funding agencies (such as foundations) may be considered, subject to NIMH review and approval. With respect to interventions research, proposals to generate pilot data, or for Phase II (feasibility), Phase III (pivotal), or Phase IV (post-approval) studies may be considered. It is advisable for investigators to first become familiar with the BTN infrastructure, its populations and clinical settings, and with its regional centers and their geography by visiting the BTN website at www.bipolartrials.org.

 

The next step is the electronic submission to the BTN-PRC of a three-page outline of the study proposal (by e-mailing the Chair and Co-Chair of the BTN-PRC), which typically will utilize the BTN-NCC at Massachusetts General Hospital for the coordination and implementation of the trial and the BTN-DCC at the Harvard Clinical Research Institute for data management and statistical analysis.

 

The outline needs to include the following elements:

1) a brief background and rationale for the proposal;

2) a description of the main reasons why the BTN is the most appropriate infrastructure for the proposed study;

3) a succinct description of the study aims;

4) a  description of the inclusion and exclusion criteria;

5) a brief overview of the study design and procedures;

6) a brief outline of the analytical plan and power analysis; and 

7) a brief outline of the budget.

 

The BTN-PRC will review each proposal to provide a concept review and determine the following:

1)     Does the proposal have adequate public health significance?

2)     Is the proposal a practical clinical trial (PCT)?

3)     Is the rationale for the use of the BTN clear?

4)     Is the proposal appropriate for the BTN? (for example, a study proposal that focuses on the study of the risk of emergence of suicidal ideation among veterans with BD and post-traumatic stress disorder would not be appropriate as the BTN clinical sites have only limited access to such a specialized patient population)

5)     Is the study feasible in the context of the BTN? (for example, a study on the fMRI changes following deep brain stimulation may not be feasible across all sites as access to neurosurgeons and fMRI expertise may be limited across RCs)

6)     Does it use BTN clinical research methods?

7)     Is the data acquisition process consistent with the BTN process?

8)     Is the division of labor for clinical personnel clearly spelled out?

9)     Are the design and methods appropriate to the BTN populations and settings?

10) In view of the portfolio of current BTN studies and BTN funding proposals currently in preparation, is the proposal appropriate for the next cycle of the specified funding agency? (for example, a study directly competing with an already-existing BTN proposal for the same cycle, review committee, and funding agency would not be appropriate)

11) Is the budget sufficient to cover the cost of the proposed work?

 

The DCC will maintain a protocol-tracking grid to facilitate BTN-PRC coordination of proposal development.

 

When proposals are submitted to the BTN-PRC, they are assigned to two primary reviewers, who are requested to provide written reviews for the BTN-PRC.  Upon completion of the primary reviews, the proposal will be reviewed by the entire committee via teleconference.  Written feedback will be provided to the investigator and to the NIMH.  The NIMH Government Project Officer (GPO) will be responsible for ensuring the completion of the programmatic review and for providing the feedback of the review to both the investigator and the BTN-PRC.

 

On the bases of these considerations, the BTN-PRC can recommend 1) approval, 2) reconsideration after modification, and 3) rejection of the concept.  These recommendations will be shared with the NIMH GPO, who will be in charge of the implementation of the NIMH programmatic review.  The approval of the BTN-PRC does not imply the approval of the NIMH programmatic review, as the NIMH considerations may be different and not necessarily overlapping.  If the proposal exceeds $500,000/year in direct costs, a specific, additional request needs to be made to the NIMH to ensure that the application will be considered.  Proposals that have received approval from both the BTN-PRC and the NIMH can be then be collaboratively developed by the applicants and the BTN into full-length proposals for submission to the NIMH or other funding agencies. The BTN-PRC will provide the investigators with feedback on the proposal itself and with specific suggestions to maximize feasibility and ease of implementation within the network.  The investigators will be required to 1) incorporate such suggestions prior to submitting their proposal to NIMH or NIH 2) to ensure that both the DCC and the NCC are included in the plan, and 3) to collaborate with the BTN-PRC to enhance the feasibility of the implementation of the proposal. Unless otherwise stated, regular NIMH or NIH proposals involving the BTN should be submitted to the NIMH on time for the standard NIMH deadlines (February 1, June 1, and October 1). In the event the total direct budget exceeds $500,000/year, only the June 1 deadline will be appropriate and will require prior authorization from the NIMH to exceed such amount. In order to provide sufficient time for review and revision, proposals should initially be submitted to the BTN-PRC at least three months prior to the standard NIMH deadlines, by March 1, July 1, and November 1.

 

BTN Data Safety and Monitoring Boards (DSMBs)

The NIMH will select Data Safety and Monitoring Boards (DSMBs), independent panels of experts to oversee and monitor the conduct of clinical trials within the BTN to ensure the safety of participants and the validity and integrity of data. The BTN DSMBs meet three times a year to consider and review protocols and consent documents for multicenter clinical trials sponsored or administered by the NIMH within the BTN. The DSMBs monitor safety issues, including the review of adverse events; the adequacy and integrity of accumulating data; and the study capabilities to test hypotheses. The purpose of this process is to assess scientific integrity and patient safety issues, and to ensure the ethical conduct of NIH/NIMH-sponsored trials. The BTN DSMBs approve study initiation and beginning subject enrollment, and determine if study procedures should be altered or stopped because of evidence of benefit or harm to trial subjects that may be attributable to one of the interventions under evaluation or reasons related to scientific integrity. The BTN DSMBs conduct independent and objective reviews of all accumulated data from specific multicenter clinical trials within the BTN, and consider requests to conduct interim analyses. The NCC responds to all DSMB issues and queries and ensures that all BTN DSMB actions and correspondences are submitted to local IRBs throughout the trial.

 

Performance Standards

All individuals and organizations involved in the BTN must follow the policies and procedures of the BTN, and terms of the relevant contracts.  Failure to comply with the established performance standards and other policies or contractual requirements governing the BTN may result in temporary or permanent discontinuation from participation in the BTN at the discretion of the BTN and NIMH.

 

Conflict of Interest

The policies and guidelines on financial disclosure and conflict of interest from each BTN member’s institution will be followed.

 

Adding Affiliate BTN Sites

Academically-affiliated institutions with experienced investigators, who are recognized nationally and internationally as scientific experts in BD clinical trials, can apply to join the BTN as additional sites in the context of proposals that have been approved by NIMH and the BTN-PRC and that involve a larger number of sites than the core  BTN sites. These sites must agree to provide “hands on” management of its clinical research staff, maintaining readiness for studies, and overseeing the implementation of studies in their affiliated clinics.  These new site PIs are responsible for all aspects of the operations and performance of their site and affiliated clinics, and their clinical research sites must include at least one academically affiliated or community-based clinic. Proposals from sites with substantial experience in BD research to join the BTN as affiliate sites are reviewed by the Site Review Sub-Committee (BTN-SRC).The BTN-SRC Chair (Deborah Wallace) and members (Drs. Terence Ketter, Charles Bowden, and Noreen Riley Harrington) will submit recommendations to the BTN Executive Committee (BTN-EC) for final review. Drs. Andrew Nierenberg, BTN-EC Chair. Drs. Charles Bowden, Terence Ketter, Joseph Calabrese, Michael Thase, and Michael Ostacher comprise the rest of the BTN-EC.

 

Scientific Misconduct

The BTN complies with Public Health Service regulations and policies for handling misconduct in research as set forth in CFR part 50, subpart A.