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BIOS Study Proposal Information and Agreements

Introduction and Rationale

The overarching rationale behind the process described in this document is to ensure that the appropriate trial Executive Committee (EC) is aware of, and has approved, all planned studies that propose to use BIOS-managed clinical trial data, and to ensure that the resulting presentations and publications reflect well on the BIOS studies and their investigators. It is important that BIOS knows how any study data will be used to protect the integrity of the data.

Furthermore, data from large multisite clinical trials represent a valuable resource, and a degree of oversight is appropriate to ensure that this resource, plus the efforts of interested investigators, is used wisely and in a way that best advances the field and adds most effectively to scientific knowledge. We wish to encourage diverse thinking and collaboration, accountability, transparency, and consistency, and to discourage duplication, wasted effort, and the risk of important data being "tied up" inappropriately, i.e., committed to an investigator but without sufficient progress being made on that investigator's planned research.

The following policies regarding access to the data are intended to provide structure to the proposal process and standards regarding security and confidentiality of the data, and to ensure that appropriate methodological and statistical approaches are employed in the analysis and interpretation of the data. A study-specific review group (SRG) will be assigned to provide feedback on the study proposal to assure that the necessary data are available to adequately and appropriately address the proposed research question, and to help researchers refine their proposal as needed. This review process further serves to alert the Executive Committee to planned projects and provide an opportunity to identify synergies between research projects and potential collaborators.

In the current research environment, increasing emphasis is appropriately being placed on being able to provide reproducible research (ASA Recommendations for Reproducible Research). Thus this document also includes policies regarding what any researcher using BIOS-managed data must provide BIOS following the completion of their research in order to ensure such reproducibility.

Definitions

Study Review Group (SRG): The primary group of Executive Committee members that is responsible for reviewing and providing feedback on the study proposal, and helping the study investigator refine the proposal, as appropriate, before review by the full committee, as appropriate and indicated below. A Senior Research Data Manager (SRDM) will be responsible for review and assurance that the requested data are available.

Formal study: A study proposal that will result in a public presentation of its results as an abstract, presentation, poster, manuscript or grant submission. Documentation of IRB approval for use of an existing, limited data set is required.

Exploratory study: A study proposal that is meant for internal understanding (within BIOS) of relationships based on trial data, and not intended to be made public.

Study investigator: Principal investigator listed on Study Proposal Form and primary contact for study process.

Senior Research Data Manager (SRDM): BIOS staff person responsible for tracking and maintaining study proposal information and status, resulting study publications, and study files required to be submitted to BIOS

Study Proposal Review Process

Timelines and the processes defined in this document are to help Bios staff to facilitate preparing the requests with appropriate approvals, unless otherwise directed and approved by the PI responsible for the data.

Study Proposal Review/Approval

The Study Proposal Form will be sent to the Senior Research Data Manager (SRDM), who will review it for completeness and set up an internal BIOS electronic storage area for any subsequent information related to the study proposal. Based on the trial data requested, the SRDM will request approval from BIOS management.

Upon initial approval by the SRG, the Study Proposal Form will be forwarded to the full EC with any comments from previous reviews. The EC will have one week to review and provide comments to the SRDM. No comment from an individual EC member within that timeframe will imply approval. Comments from the EC members will be reviewed by the SRG to determine the status of the proposal and if revisions are required. Any further revisions will be reviewed by the SRG. If feasible with respect to the timing of EC meetings, the study investigator may be asked to make a formal presentation of the intended study. However, any further suggested refinements will not impact the previous approval of the study.

Upon final approval, the SRDM will confirm with the study investigator the data fields to be provided and will coordinate preparation of the data set. The study investigator will then send a signed Data Use Agreement form to the SRDM. The data set will then be sent to the study investigator with appropriate metadata and data definitions, and a copy of the data will be included in the study's BIOS folder.

Minor changes in the study's research initiatives or requests for minor amounts of additional data should be submitted in writing to the SRDM who will forward it to the SRG for approval. Major changes or requests for additional data will require submission of a new Study Proposal Form.

Abstract

The Study Proposal Form will be completed and sent to the SRDM, who will review it for completeness and set up an internal BIOS electronic storage area for any subsequent information related to the study proposal. A draft abstract will be sent to the SRDM for BIOS review and included in the study's folder. Allow at least one week for this review. The study investigator will notify the SRDM upon acceptance of the abstract. They are also responsible for submitting the files used in preparing the abstract submission to BIOS (see Required Submissions to BIOS).

Presentation/Poster

A draft copy of the presentation/poster will be sent to the SRDM for BIOS review, and a copy will be included in the study's file. Allow at least one week for this review. The study investigator is responsible for appropriately recognizing the BIOS trials whose data are used in the presentation (see Acknowledgements, Source of Funding and Disclosures), and will provide the SRDM with a final copy of the presentation/poster for the study's file. They are also responsible for submitting a copy of the presentation/poster to BIOS.

Manuscript

Once the manuscript has been approved by all study co-authors, a copy must be sent to the SRDM, who will forward it to an assigned SRG for review and approval before submission. The study investigator should allow at least a month for feedback and review of subsequent revisions. Although the SRG will be the main reviewing body, at the discretion of the SRG, the manuscript may be sent to the EC, or select members of the EC, for additional feedback. A copy of the submitted manuscript must be sent to the SRDM for the study's files. An electronic copy of the final published manuscript and citation must be sent to the SRDM for the study's file. The study investigator is responsible for appropriately recognizing the BIOS trials whose data are used in the manuscript (see Acknowledgements, Source of Funding and Disclosures). They are also responsible for submitting the files used in preparing the manuscript to BIOS (see Required Submissions to BIOS). Lead co-authors are responsible for complying with the NIH Public Access Policy (http://publicaccess.nih.gov/).

Grant Submission

A draft copy of the grant application that will be using BIOS data must be sent to the SRDM, who will forward it to an assigned SRG for review and approval before submission to the funding agency. The study investigator should allow at least one month (or other coordinated timeframe) for feedback and review of subsequent revisions. An electronic copy of the submitted grant application must be sent to the SRDM for the study's files. The study investigator will update the SRDM as to the status of the submission, and will provide the SRG with any proposed revisions to the grant submission based on agency reviews. An electronic copy of the final accepted grant application will be sent to the SRDM for the study's file. The study investigator is responsible for appropriately recognizing the BIOS trials whose data are used in the grant application (see Acknowledgements, Source of Funding and Disclosures). They are also responsible for submitting the files used in preparing the BIOS-related segments of the grant application to BIOS (see Required Submissions to BIOS). The EC must be notified of any accepted grant application.

Required Submissions to BIOS

Besides the above notifications and publication copies, the study investigator is responsible for providing the following to the SRDM for purposes of reproducible research:

- Data set(s) used for final analyses
- Metadata and codebooks for these data sets relating original variables to final versions and defining any new variables that were derived from BIOS-provided data.
- Program(s) that track changes from BIOS-provided data, the creation of new variables, and the preparation of analyses, tables and graphs of final results

Acknowledgements, Source of Funding and Disclosures

1. ACKNOWLEDGEMENTS

We thank the patients and families who volunteered for this study, Genentech Inc. for the donation of study drug (alteplase), and [list anyone else who contributed to your work here].

2. SOURCE OF FUNDING

All publications and presentations utilizing data supplied by BIOS should include the following information for the relevant trials in a SOURCE OF FUNDING section:

CLEAR Intraventricular rt-PA Safety Study
Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage - Intraventricular rt-PA Safety Trial (CLEAR-IVH Safety) was supported by grants FD-R-001693 awarded to Dr. Daniel Hanley from the Office of Orphan Products Development, Food and Drug Administration.

CLEAR Intraventricular rt-PA Pharmacokinetic Study
Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage - Pharmacokinetic Study (CLEAR-IVH PK) spanned the CLEAR-IVH Safety trial and the CLEAR A trial, and was supported by grants FD-R 002018 awarded to Dr. Daniel Hanley and Dr. Denise Rhoney from the Office of Orphan Products Development, Food and Drug Administration.

CLEAR Intraventricular Hemorrhage Thrombolysis Trial Part A and B
Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage -The Intraventricular Hemorrhage Thrombolysis Trial (CLEAR A and B) was supported by grants FD-R-001693 awarded to Dr. Daniel Hanley and Dr. Neal Naff from the Office of Orphan Products Development, Food and Drug Administration.

MISTIE II/ICES
Minimally Invasive Surgery and rt-PA in ICH Evacuation Phase II (MISTIE II) was supported by grants R01NS046309 awarded to Dr. Daniel Hanley from the National Institutes of Health (NIH)/National Institute of Neurological Disorders and Stroke (NINDS). ICES was led by Co-Principal Investigator Dr. Paul Vespa at the University of California Los Angeles.

CLEAR III
Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage Phase III (CLEAR III) is supported by the grant 5U01 NS062851-05 awarded to Dr. Daniel Hanley from the National Institutes of Health (NIH)/National Institute of Neurological Disorders and Stroke (NINDS).

MISTIE III

Minimally Invasive Surgery and rt-PA in ICH Evacuation Phase III (MISTIE III) is supported by the grant 5U01 NS080824-02 awarded to Dr. Daniel Hanley from the National Institutes of Health (NIH)/National Institute of Neurological Disorders and Stroke (NINDS).

3. DISCLOSURES

Dr. Daniel F. Hanley was awarded significant research support of grants R01NS046309, 5U01 NS062851-05, and 5U01 NS080824-02. Johns Hopkins University holds a use patent for intraventricular tissue plasminogen activator.

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