How To Write A Protocol For A Health Care Program

Transcription

1 Resource for Clinical Investigation in Blood and Marrow Transplant MANUAL OF PROCEDURES Version 1.0 dated September 27, 2007 CENTER FOR INTERNATIONAL BLOOD & MARROW TRANSPLANT RESEARCH National Marrow Donor Program 3001 Broadway St. N.E., Suite 110 Minneapolis, MN USA (612) Medical College of Wisconsin P.O. Box Watertown Plank Road Milwaukee, WI USA (414)

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3 TABLE OF CONTENTS 1. ORGANIZATION Mission Statement and Organizational Overview RCI BMT Clinical Trials Office RCI BMT Office Clinical Trials Staff Trial Centers Clinical Trial Advisory Committee (CTAC) Study Administration Protocol Team Data and Safety Monitoring Board (DSMB) Purpose Central Institutional Review Board (IRB) Guidelines for Reporting Adverse Events to Institutional Review Boards STUDY CONCEPT DEVELOPMENT AND APPROVAL Developing a Proposed Study Concept Contents of a Study Concept Proposal Review Review Packet Review of the Study Concept by the Clinical Trials Advisory Committee (CTAC) Review of CTAC approved proposals by the CTO Review Cycle PROCEDURES FOR IMPLEMENTING APPROVED STUDY CONCEPTS Tasks Following Approval of a Study Concept Establishment of a Protocol Team Development of a Protocol Primary Draft Working Draft Final Draft DSMB Review Development of Case Report Forms (CRFs) and Study Database Study Budget Preparation, Management of Contributions and Procurement Guidelines Study Budget Preparation and Revisions Procurement Guidelines Management of Contributions Protocol Specific Costs Travel Contributions Budget Review Process i

4 Expenses Budget Revisions Protocol Amendments Procurement Guidelines for RCI BMT Office Trial Initiation Preparation Activities Identification of Extra-Network Services Addressing Regulatory Requirements Site Identification Protocol Specific Site Training Ancillary Studies Definition Process for Initiation and Approval Funding for Ancillary Studies Ancillary Study Monitoring Manuscript Approval and Publication Data Analysis and Publication Issues PROCEDURES FOR APPROVAL OF PROTOCOL AMENDMENTS Proposal of a Protocol Amendment Review of Proposal for Protocol Amendment Finalizing the Protocol Amendment Regulatory Authorities and Documents Case Report Form (CRF) Revisions Protocol Budget Revisions Extra Services Revisions Initiation and Accrual Activity Revisions Additional Site Training SITE MONITORING Initiation Site Visits Follow-up Monitoring Visits Data Quality Assurance Data Editing Missing Forms Evaluation of Center Performance ADVERSE EVENT REPORTING Definition of Adverse Event Adverse Event Definitions Unexpected Adverse Events ii

5 6.3. Expected Adverse Events Monitoring Adverse Events Adverse Event Reporting and Management FDA IND/IDE Reporting Monitoring Toxicity Guidelines for Reporting Adverse Events to Institutional Review Boards Adverse Event Documentation Providing Follow-up Information to Local IRBs Early Phase Multi-Center Clinical Trials Requests from an IRB for Additional Information HUMAN SUBJECT PROTECTION AND REGULATORY PROCEDURES Institutional Review Board Health Insurance Portability and Accountability Act (HIPAA) Office of Human Research Protections (OHRP) Institutional Assurances Participation of Women, Ethnic Minorities and Children Site Regulatory Documents Investigational New Drug or Investigational Device Exemption Application PUBLICATIONS, PRESENTATIONS, ABSTRACTS, DATA REQUESTS AND SAMPLE REQUESTS Guidelines Amendments to Guidelines Continuing Review Regarding Formal Presentation of Data and the Assignment of Writing Teams Policy Regarding Oral Presentation of RCI BMT Related Data General Policy Approvals and Submission Manuscript Requirements Titles Acknowledgments Manuscripts Describing Data from CIBMTR RCI BMT Trials Data Analysis Writing Responsibilities Acknowledgement of Donations and Other Protocol Support Donations Data and Publications Attributions Timelines Authorship Authorship Eligibility Requirements Establishing the Order of Authors iii

6 Removing Authors Authorship on Joint Studies Abstracts, Public Presentations, Electronic Postings General Abstracts Public Presentations and Electronic Postings of Study Data Ancillary Studies, Laboratory Studies, Position Papers and Technical Reports General Data Requests Types of Data Available Stipulations for Data Requests Requesting Data Access to Data and Classification of Data Types of Data Requests Sample Requests Types of Samples Available Overview of the Request Process Requesting Samples Access to Samples Restrictions Disclaimer Acknowledgements How Requests Are Reviewed/Approved for Samples and Corresponding Data How Samples Are Distributed to Requestor Definitions Journal Articles Presentations Electronic Media CIBMTR RCI BMT SHIPPING INSTRUCTIONS USING FEDERAL EXPRESS APPENDIX A APPENDIX B APPENDIX C APPENDIX D Clinical Trials Advisory Committee Charter Data Safety Monitoring Board Charter Study Proposal Application and Template Financial Disclosure Example iv

7 CHAPTER 1 RCI BMT ORGANIZATION

9 1. ORGANIZATION 1.1. Mission Statement and Organizational Overview The Center for International Blood and Marrow Transplant Research (CIBMTR) was established to bring together the research efforts of the International Marrow Transplant Registry (IBMTR) of the Medical College of Wisconsin and the research arm of the National Marrow Donor Program (NMDP). The affiliation represents a commitment of the two organizations to coordinate their efforts and resources and to provide a single point of focus for development and support of transplant related clinical research. Well-planned and coordinated multi-center phase I and II studies are critical for advancing the field of hematopoietic cell transplantation. To facilitate such studies, the CIBMTR formed the Resource for Clinical Investigations in Blood and Marrow Transplant (RCI BMT) to provide statistical expertise and data management services for multi-center phase I/II trials. The organizational structure of the CIBMTR is shown in Figure 1.1. Of the four major areas of research activity, Clinical Trial Support facilitated by RCI BMT will be addressed in this Manual of Procedures (MOP). Figure 1.1 CIBMTR Organizational Structure Assembly NMDP Research Joint Affiliation Committee Executive Director MCW IBMTR Advisory Committee Executive Committee Senior Research Advisor Nominating Committee Chief Scientific Director Chief Statistical Director Working/Steering Committees Consumer Advocacy Committee International Studies Committee Observational Research Immunobiology Statistical Methodology Clinical Trials Support Clinical Outcomes Health Policy BMT CTN* RCI BMT * = The BMT CTN Data and Coordinating Center is a Collaboration of CIBMTR, NMDP and the EMMES Corporation OrgCht07_29.ppt 1-1

10 1.2. RCI BMT Clinical Trials Office The Clinical Trials Office (CTO) is responsible for the daily operation of prospective studies being facilitated by the RCI BMT. The CTO formulates and implements all policy decisions related to the work of the CTO. The Clinical Trials Office Leadership consists of: Marcie Tomblyn, MD, MS Mary Horowitz, MD, MS Daniel Weisdorf, MD Dennis Confer, MD Mary Eapen, MD, MS Rebecca Drexler, BS Brent Logan, PhD Gordy Bryan The functions of the CTO include: Develop and maintain a Manual of Procedures Ratify major changes in the Manual of Procedures CIBMTR Assistant Scientific Director and Program Director for the RCI BMT CIBMTR Chief Scientific Director CIBMTR Senior Advisor NMDP Chief Medical Officer CIBMTR Assistant Scientific Director CIBMTR Minneapolis Program Manager CIBMTR PhD Statistician NMDP and CIBMTR Chief Financial Officer Initial review of concept proposals for preliminary feasibility, scientific interest, and competing protocols. This review includes selection of CIBMTR Working Committee Chairs to provide a formal written review prior to Clinical Trials Advisory Committee (CTAC) review. Review Concept Proposals recommended by the CTAC (see section 2.3.2) Identify the following protocol team members for approved proposals: - Provide a Protocol Statistician for each study who has primary responsibility for statistical design and analysis - Provide a Protocol Officer for each study who may serve as the Medical Monitor for the study and has primary responsibility for keeping the Protocol Team informed about the progress of the trial - Provide a Protocol Coordinator for each study who has responsibility for overseeing all aspects of developing the protocol document and serves as primary site liaison Resolve operational problems brought by investigators, clinical research associates, or laboratories/repositories. Monitor the performance of all participating centers. This includes assessment of the quality of data collected by center staff and adherence to all protocols. Assure study results are reported in the scientific literature in a timely manner. The CTO Leadership is supported by the CIBMTR Minneapolis research staff including Senior Clinical Research Specialists, Clinical Research Specialists, and Clinical Research Assistants. 1-2

11 The CTO Leadership will meet at least three times a year to approve and prioritize proposals, monitor the progress of studies and consider special issues that may arise. Additional meetings may be held as necessary. The CTO does not have access to blinded data from studies RCI BMT Office Clinical Trials Staff The staff plays a key role in developing and facilitating study protocols and is responsible for statistical planning and the collection of quality data from participating centers. Functions are performed by staff at the CIBMTR Minneapolis and Milwaukee offices. In addition, staff from appropriate NMDP departments will support the activities of the RCI BMT Office. Staff responsibilities include but are not limited to the following: Maintain a computerized roster of participants with relevant contact information, RCI BMT roles and organizational affiliations Collaborate with the CTO in developing study protocols, procedures, reports, manuscripts and Manual of Procedures Schedule meetings and conference calls, determine site locations for meetings and provide travel arrangements for meetings Coordinate communications among participating centers Coordinate and support the work of Protocol Teams. Prepare and submit applications to NMDP Institutional Review Board (IRB) and the RCI BMT Data and Safety Monitoring Board (DSMB). Provide site support for internal review board submissions including IRB. Provide representatives from appropriate NMDP departments to support studies in aspects specific to their department. Perform site selection, initiation, close out and interim monitoring visits. Coordinate the implementation of studies including: - Develop contracts with centers - Identify suitable labs and repositories for support of studies - Develop contracts with identified labs and repositories - Coordinate communications among laboratories and repositories - Develop data collection forms and participate in clinical database management system development process - Coordinate the training and certification of center staff in standardized data collection and quality control procedures - Review all data submitted on case report forms for completeness and accuracy - Communicate with participating centers regarding missing, delayed, incomplete, or erroneous data - Monitor adverse events and participating center reporting - Prepare periodic reports on the performance of participating centers 1-3

12 - Coordinate site activation activities including site initiation training - Analyze study data - Assist in preparing scientific reports for publication 1.4. Trial Centers All CIBMTR domestic centers will be considered eligible for participation in trials although not all trials will be opened in all centers. Selection for participation in specific protocols will be determined by: Study design and requirements Level of commitment Potential accrual Competing protocols Previous record of participation in multicenter HCT trials 1.5. Clinical Trial Advisory Committee (CTAC) The CTAC is responsible for assessing submitted proposals for scientific merit, feasibility, and alignment with scientific agenda, advising the RCI BMT CTO on priority of proposed studies and reviewing progress of ongoing studies. Full details of the committee organization and function are in the CTAC charter (Appendix A) Study Administration The organizational structure for administration of RCI BMT studies includes a Protocol Team, an independent DSMB, central IRB oversight and communication with local IRBs as outlined below Protocol Team A Protocol Team will be appointed for each approved Study Proposal. The Protocol Team has primary responsibility for preparation of protocol documents, for addressing operational issues during enrollment including preparation of study amendments and reports to the DSMB, for analysis of study data and for preparation of manuscripts. The Team will consist of: Protocol Chair Center Investigators with limit of two representatives from each center. Protocol Officer (CIBMTR Scientific Director) Protocol Statistician (CIBMTR Statistician) Protocol Coordinator (CIBMTR CTO Staff) Ad hoc members as deemed necessary by the Protocol Chair Data and Safety Monitoring Board (DSMB) Purpose The DSMB is an independent board created and managed by NMDP Office of Investigator Sponsored Research. The primary function of the board will be to perform ongoing assessment and monitoring of active CIBMTR RCI BMT studies relative to scientific merit/validity, safety 1-4

13 and efficacy. All RCI BMT protocols must be reviewed and approved by the DSMB prior to central IRB review (section 1.6.3). Full details of the committee organization and function are in the DSMB charter (Appendix B) Central Institutional Review Board (IRB) The NMDP IRB is an administrative body established to protect the rights and welfare of human subjects recruited to participate in research activities under the auspices of the National Marrow Donor Program. The NMDP IRB has the authority to approve, require modifications in, or disapprove all research activities that fall within its jurisdiction as specified by both federal and state regulations and NMDP polices and procedures. The NMDP IRB serves as a central IRB for all RCI BMT protocols. NMDP IRB approval of and RCI BMT protocol is required prior to protocol distribution to participating sites for local IRB approval Guidelines for Reporting Adverse Events to Institutional Review Boards Introduction All IRBs associated with each RCI BMT trial will be provided with the following information: A description of the DSMB procedures; Identification of the DSMB members' areas of expertise, excluding names; and Feedback after each DSMB meeting. In addition, the Office of Human Research Protection (OHRP), DHHS issued a memorandum Dated May 22, 2000, Continuing Review of DSMB-Monitored Clinical Trials, which authorizes IRBs to: Rely on current statements from DSMBs that the DSMBs have reviewed study-wide adverse events, interim findings and any recent literature that may be relevant to the research. Of note, these procedures are in addition to local IRB adverse event reporting requirements. Providing Follow-up Information to Local IRBs If the DSMB does not identify any safety or other protocol-related concerns, within 30 days after a DSMB meeting, the Executive Secretary will prepare a Summary Report that will state that: A review of outcome data, adverse events, and information relating to study performance (e.g., data timeliness, completeness, and quality) across all centers took place on a given date; The observed frequency of adverse events did not exceed what was expected and indicated in the informed consent; A review of recent literature relevant to the research took place; and The DSMB recommended that the study continue without modification of the protocol or informed consent. The report will be distributed to each participating center s Principal Investigator (PI). It is the responsibility of each PI to forward this information to their local IRB. 1-5

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16 CHAPTER 2 STUDY CONCEPT DEVELOPMENT AND APPROVAL

18 2. STUDY CONCEPT DEVELOPMENT AND APPROVAL 2.1. Developing a Proposed Study Concept Proposals for clinical trials may be submitted from members of CIBMTR centers, NMDP Network, Pharmaceutical Companies or other researchers. The efficient development of a proposed study idea into a document that enables review by the CTAC and priority ranking is one of the primary activities of the RCI BMT. This chapter provides detailed descriptions of the process, timeline and documentation required to develop protocol ideas received by the RCI BMT Contents of a Study Concept All ideas for studies must be submitted to the RCI BMT using the Prospective Study Proposal Application and Template available on the CIBMTR web site (Appendix C). The Protocol Summary includes the following information: Submitting individual's name and affiliation Submitting individual's contact information (phone, fax, ) Proposed study title A one to two page background and rationale section Hypotheses to be tested Primary objective Primary outcome measure Secondary objectives Secondary outcome measures Patient population, including diagnosis and disease state, type of transplant, other inclusion and exclusion criteria Statistical section including sample size calculations, and important variables for consideration in stratification (if applicable) Possible funding sources Upon receipt of a Proposal, RCI BMT staff is responsible for: Creating a file folder for the study; Assigning a Study Proposal Number for tracking the study concept through review; Informing the submitting individual regarding receipt of their proposal; Obtaining potential accrual information from the Observational Database of CIBMTR; Forwarding the completed Protocol Summary to an RCI BMT Scientific Director and appropriate CIBMTR Working Committee Chairs to evaluate potential numbers of patients, competing studies and scientific interest; 2-1

19 If necessary, requesting additional information or clarification from the submitting individual; Adding accepted proposals to the agenda of the next CTAC meeting for formal scientific review Proposal Review Review Packet Using information obtained from the internal review and Working Committee Chairs, a study packet is prepared by RCI BMT staff for use during CTAC review. This packet contains: Submitted proposal; Summary of comments from Working Committee Chair review; Estimate, based on inclusion and exclusion criteria, potential numbers of eligible study participants are available. This summary will include the top ten potential centers within the CIBMTR network. Additionally, if centers have verbally committed to the proposal PI to participate, potential numbers of eligible study participants from these centers are included. Summary of other considerations if applicable. This may include competing protocols, central pharmacy, specialized lab testing, IND/IDE requirements, etc Review of the Study Concept by the Clinical Trials Advisory Committee (CTAC) The submitting individual or his/her designee presents the Study Concept Report to the CTAC. The CTAC reviews the Proposal for scientific merit, feasibility, and alignment with the scientific agenda of the CIBMTR RCI BMT. The relative importance of the following three areas of evaluation is determined. It is expected that scientific merit will be the primary consideration after which the remaining two areas will be considered equally. A Study Proposal must be approved by a majority of CTAC members. 1. Scientific Merit: The Scientific Merit of the Study Proposal will be designated following the NIH system for RO1 grant applications, i.e. using a rating. Assessment of scientific merit will include consideration of the scientific direction developed for the RCI BMT by the CIBMTR Executive Committee and the RCI BMT CTO. 2. Feasibility: The feasibility of the proposed study will be based on consideration of the potential for accrual and ability of centers to conduct the proposed treatment interventions (e.g., studies requiring specialized graft manipulations available at only one center may be viewed as less feasible than a trial utilizing only standard graft manipulations). Budget considerations are also important in assessing feasibility since the RCI BMT is not a funding agency. 3. Willingness of Identified Centers to Participate: The individual proposing the study is encouraged to provide the CTAC with letters of support from centers indicating their anticipated participation and accrual. Additionally, using the CIBMTR database, up to 10 US transplant centers will be identified for possible participation based upon the patient population and estimated accrual. A sufficient number of centers must be willing to participate for the protocol to be approved. 2-2

20 Review of CTAC approved proposals by the CTO All proposals approved by the CTAC are then reviewed by the CTO. The CTO will prioritize approved proposals based on staffing, finanacial support, and scientific merit. Studies will be assessed for relevance to the mission of the RCI BMT. If necessary, studies may be referred for consideration by other clinical trials mechanisms including the BMT CTN or the NMDP Office of Physician Initiated Research Review Cycle Parties can propose study concepts at any time. While Study Proposal preparation and their review will begin shortly after receipt of the Protocol Summary Form, this does not guarantee a study will be conducted. The CTAC will review Study Proposals at each CTAC meeting (Appendix A). After CTAC approval, review by the CTO occurs. After each step of the review process, investigators will be notified of the current status of their proposal within 10 working days of the decision. All notifications will occur via both electronic and postal mail. 2-3

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22 CHAPTER 3 PROCEDURES FOR IMPLEMENTING APPROVED STUDY CONCEPTS

24 3. PROCEDURES FOR IMPLEMENTING APPROVED STUDY CONCEPTS 3.1. Tasks Following Approval of a Study Concept Approval of a Study Proposal by the CTAC and, subsequently, the CTO requires several activities to be initiated. While outlined below as separate activities, in practice, they are carried out concurrently to the extent possible. Tasks include: Establishment of a Protocol Team Assignment of a Study Number Development of a Study Protocol Identification and procurement of services that will be required from outside providers Development of Case Report Forms and the Study Database Study Budget Preparation Preparation of study-related educational materials by the Office of Patient Advocacy Addressing Regulatory Requirements Site Identification Contracts with participating sites Site Training and Activation Establishment of a Protocol Team Each approved Study Proposal has a Protocol Team responsible for protocol development, oversight of the trial, and analysis and publication of the study results. The Protocol Team includes the following members: Protocol Chair: the CTO appoints the Protocol Chair. This individual will, in general, be the person who submitted the Proposal. The Protocol Chair has primary responsibility for the study throughout its course, including but not limited to, preparing agendas and chairing meetings of the Protocol Team, reviewing Protocol Drafts prepared after discussions of the Protocol Team, presenting progress reports on protocol development to the CTAC, leading Investigators Meetings for the protocol, addressing issues raised by the Protocol Officer, Protocol Coordinator, investigators at participating centers, and/or the DSMB and writing the primary study manuscript Center representatives: One to two Center representatives will serve as co-investigators on the Protocol Team to help develop the protocol document, supervise the study throughout its course and interpret and present study results. Protocol Officer: A CIBMTR Scientific Director is assigned as the Protocol Officer for the study. Responsibilities of the Protocol Officer include: - Serving as the Medical Monitor for the study, provided there is no conflict. If there is a conflict, the CTO will appoint an alternative Medical Monitor. - Providing an additional level of scrutiny of the proposed protocol specifications, specifically addressing whether they are sufficient to accomplish the scientific objectives of the study 3-1

25 - Monitoring delays in protocol development/review/accrual and addressing obstacles to progress promptly in consultation with the Protocol Chair - Communicating with the Protocol Chair regarding the status and progress of the trial - Presenting protocol progress to the CTO and the CTAC - Preparing materials for the DSMB A Medical Monitor will be assigned to each RCI BMT protocol. The Medical Monitor will be a qualified physician who is familiar with blood and marrow transplantation and is also familiar with the conduct of clinical research and regulatory requirements for safety reporting. The Medical Monitor will not enroll patients in RCI BMT protocols. The Medical Monitor can also be the Protocol Officer. The Medical Monitor for RCI BMT studies will: - Review safety sections of protocols and help develop appropriate safety stopping rules as needed - Assist with protocol amendments as they relate to safety issues - Review all unexpected Serious Adverse Events (SAEs) associated with the protocol and provide an unbiased written report regarding the relationship to the test product within 48 hours of receipt - Write narrative descriptions of unexpected Serious Adverse Events for inclusion into study-related documentation - Provide consultation for safety issues of medical concerns during the course of the clinical trial The written evaluations of the Medical Monitor will be returned to the RCI BMT for appropriate reporting to the RCI BMT Clinical Trials Staff. Follow-up information may be requested and will be obtained by the Protocol Coordinator and sent to the Medical Monitor for review. Protocol Statistician: A CIBMTR PhD statistician is designated as the Protocol Statistician. The Protocol Statistician has primary responsibility for the study s statistical design and analysis. For some protocols, a secondary Protocol Statistician may also be designated. The Protocol Statistician interacts and communicates with the secondary PhD statistician on a regular basis regarding issues of statistical design and for secondary review of the final study analysis plan and analysis. The Protocol Statistician also assists in preparing materials for the DSMB. Protocol Coordinator: The Protocol Coordinator is a member of the CIBMTR RCI BMT Office. The Protocol Coordinator has responsibility for overseeing all aspects of developing the Protocol Document, from initial concept though production, internal and external review, revision, approval, and final dissemination. This includes preparing revised drafts of the protocol pursuant to discussions of the Protocol Team and ensuring completeness and internal consistency of the protocol and conformity with standards of protocol production and stated CIBMTR RCI BMT policies and procedures. The Protocol Coordinator prepares regulatory documents as needed and prepares protocol documents for meetings of the Protocol Team, CTAC, CTO, and DSMB. Other members are appointed to the Protocol Team, if necessary, for specific expertise related to the study. 3-2

26 The Protocol Team meets by teleconference as soon as possible after formation and at frequent intervals thereafter. The Protocol Officer is responsible for requesting scheduling of conference calls by the CIBMTR Administrative Support staff Development of a Protocol The Protocol Document is the primary study document used to guide conduct of the trial. Participating sites use the Protocol Document when preparing their submission for their Institutional Review Boards (IRBs). No changes to the Protocol Document by a participating site are allowed without prior written approval of the Protocol Chair and the Protocol Officer with the exception of reformatting and revising the sample Informed Consent document to be compliant with local IRB requirements. All revised Informed Consent documents must be reviewed by the RCI BMT office prior to submission to the local IRB to determine that key elements are preserved Primary Draft The Protocol Team is responsible for generating the first draft of the protocol based on the Study Concept Report and comments from the CTAC and CTO. Many of the critical elements of the Protocol will be contained in the Study Concept Report. The Protocol will follow the CIBMTR RCI BMT protocol template, which is available from the CIBMTR RCI BMT Office. The Protocol Chair prepares a primary Draft Protocol for distribution to the members of the Protocol Team for review and discussion in advance of the first Protocol Team teleconference. Prior to distribution, the following are done: The Protocol Officer and the Protocol Coordinator review the Preliminary Draft Protocol for medical/safety issues, agreement with the Study Concept Report, potential protocol design and feasibility issues. The Protocol Statistician drafts a Statistical Considerations section based on the Study Concept Report, Protocol Team and CTAC comments and Draft Protocol. The Statistical Considerations section will include sample size estimates and justification, randomization (if required), analysis of primary outcome measure, plans for interim analyses (if required) and stopping rules (if required) Working Draft After the first Protocol Team conference call, the Protocol Coordinator, with assistance from the Protocol Chair and/or Protocol Officer, incorporates revisions discussed and agreed to on the conference call. This Working Draft Protocol is then circulated to the Protocol Team for further discussion and comment during team conference calls or via communications. Multiple iterations of the draft protocol are generally necessary to develop a final Protocol Document. The Working Draft Protocol will also be reviewed at a CIBMTR weekly statistical meeting prior to final approval by the Protocol Team. The final approval by the Protocol Team is a document that will be maintained by the RCI BMT Office for the duration of the study and serves to document acceptance of key portions of the protocol. This document can be received by fax or . The final protocol draft is then submitted to the DSMB. Recommendations from the DSMB are discussed by the Protocol Team and changes incorporated into the Protocol as necessary prior to 3-3

27 central IRB submission. If necessary, an updated document of the Final Approval by the protocol team will be obtained after DSMB recommendations Final Draft The Protocol Coordinator prepares the final Draft Protocol Document including a Study Number and Version Date. The Protocol Document includes: Synopsis that concisely outlines the study design and objectives Background, scientific rationale, and objectives for the study Detailed description of the treatment preparations and dosing Detailed description of the experimental design Careful clinical definition of all primary and secondary endpoints Detailed eligibility (inclusion/exclusion) requirements for participation Follow-up schedules and requirements for patient monitoring Required clinical exams and specimen submission schedules Safety measurements, monitoring procedure and unexpected Grades 3-5 adverse events reporting procedures Details of registration and randomization procedures Procedures for blinding study treatments Detailed statistical considerations including an Analysis Plan Sample informed consent References and appendices, as appropriate DSMB Review The DSMB is a standing committee appointed by the NMDP Office of Investigator Sponsored Research (see Chapter 1). Once the protocol team has finalized the protocol document, it is sent to the DSMB for consideration of safety and monitoring issues. The protocol cannot be implemented until the DSMB has approved the Final Protocol Document Development of Case Report Forms (CRFs) and Study Database Development of Case Report Forms (CRFs) and the Study Database begin once the Working Draft Protocol is available. CRFs are designed based on CIBMTR/NMDP Report Form format and definitions. The Protocol Coordinator is responsible for the following items with regards to CRF and database development: Coordinating with NMDP Contracts development of a Scope of Work and rider document to the EMMES Agreement for Database development. Contacting the EMMES Project Officer to support the Protocol Team for design and implementation of the study database and electronic CRFs Drafting the initial version of the CRFs based on the Working Draft of the Protocol Obtaining input on CRFs from the Protocol Team 3-4

28 Drafting secondary versions of CRFs based on any changes required by the Protocol Team Once the Study Protocol has been approved by the DSMB, making any final changes to CRFs Pilot CRFs with a subset of Center CRAs Forwarding final changes to the EMMES Project Officer database programmer after final draft of CRFs are reviewed by the Protocol Officer and the Protocol Statistician 3.4. Study Budget Preparation, Management of Contributions and Procurement Guidelines Study Budget Preparation and Revisions In conjunction with the RCI BMT, the NMDP Finance Department, which includes Contracts and Purchasing, shall be responsible for Study budget development and reporting. This shall include individual protocol budgets and coordination with external funding groups/agencies Procurement Guidelines Budgets shall be prepared and approved for each project. The budget must include all costs needed for internal labor, travel and protocol-specific expenses on an annual basis including any items that are to be contracted to outside organizations, including laboratory, central pharmacy, or other products and services needed to accomplish the objectives of the Study Management of Contributions The CIBMTR Financial Officer (i.e. meaning his/her designee throughout) and the CIBMTR Program Manager shall coordinate the budget process. A meeting shall be set up either by teleconference or in person with the appropriate parties, including but not limited to the NMDP representatives from Finance and Contracts, the Protocol Chair, Protocol Officer, Protocol Coordinator, and the RCI BMT Director. The applicable budget forms shall be filled in as completely as possible during this meeting. Form titles include, but are not limited to: Protocol Budget Set of Questions Laboratory Budget Set of Questions Product or Services Set of Questions Protocol Specific Costs The draft budget shall contain, as applicable: Written budget assumptions - Projected enrollment - Number of sites and the number of start-ups to be allocated - Expected contributions - Central laboratories - Central pharmacy - Packaging and shipping - Any other assumptions having an impact on the budget Startup budgets* will be $ per center and shall include: 3-5

29 - Labor hours for the physician, sub-investigator, clinical research coordinator and/or data manager as appropriate - Supply budget (depending on the complexity of the study, number of nonstandard of care laboratory draws, number of containers for shipping, etc.) - Investigational drug pharmacy fee Per-patient budgets*, shall include: - Labor hours for the physician, sub-investigator, clinical research coordinator and/or data manager. Fringe benefit costs should be included in the labor rate. - TC administrative expenses at the current agreed to rate should be added to the labor hours. - Special laboratory tests required by the protocol, done at the transplant center sites - Non-standard of care drug administration costs - RCI BMT Support costs - Costs for the central laboratory, pharmacy, shipping, etc. - Appropriate NMDP indirect rate Standard of care tests, drugs, pharmacy costs, etc. shall not be included in the budget. Application of financial contributions: - Upon a verbal commitment of contributions from outside entities, the budget shall be credited. However, the Assumptions sheet shall clearly reflect that the contributions are only an assumption, and that the Study may not proceed without a final commitment of the contributions. - Upon finalization of the contributions the budget and corresponding assumptions shall reflect this commitment. - CIBMTR contracts will keep with the NIH policy and be limited at 28% for Indirect costs *Note: The startup and per-patient budgets are estimates used for budget development purposes only. The individual sites may apply the funds however they deem appropriate to perform the protocol-specific tasks Travel All Study travel must be included in the budget. Travel arrangements may be made through NMDP s on-site travel agency under the direction of the RCI BMT Office Contributions The Protocol Chair or his/her designee shall determine if any potential contributors are to be approached for contributions to the Study. If a contributor is identified, the Protocol Chair or designee shall work with the NMDP Contracts Department to negotiate a Memorandum of Agreement (MOA) with the contributor. Under the direction of the CIBMTR Financial Officer, NMDP Contracts shall negotiate the MOA, utilizing the expertise of the Protocol Chair or other designees. Financial contributions shall be held at the NMDP in a designated account, to be utilized for costs related to that protocol, unless otherwise approved by the Contributor. 3-6

30 Budget Review Process The final budget must be signed off by the RCI BMT Director, the CIBMTR Chief Scientific Director, the CIBMTR Financial Officer, and the Protocol Officer ( Budget Committee ). Upon approval of the study by the DSMB, the CIBMTR RCI BMT shall work with the NMDP Contracts and Finance Departments to proceed with the Request for Proposals and contracts for centralized services, shall finalize contributions, and shall review the budget for any final revisions Expenses The NMDP shall track and reconcile the RCI BMT Office protocol-related funds, make payments to suppliers and reconcile all costs quarterly Budget Revisions When a significant* change is made to the budget, either because of contributions, or a change in costs, a new budget shall be routed for signature by the RCI BMT Director, the CIBMTR Chief Scientific Director, the CIBMTR Financial Officer, and the Protocol Officer. Major increases in cost must be approved by the CIBMTR Financial Officer and CIBMTR Chief Scientific Director *If funds are already committed by the NMDP to the project, the budget does not have to be reapproved. If additional funds are not committed, the budget must be rerouted for approval for any additional projected expenditures Protocol Amendments The Protocol Chair, Protocol Officer, and Protocol Coordinator will be responsible for reviewing the protocol amendment to determine if any changes will affect the protocol budget. If changes are required, the specifics of the changes forwarded to the CIBMTR Financial Officer, and the change procedure outlined in the paragraph above shall be followed Procurement Guidelines for RCI BMT Office The RCI BMT Office will be responsible for securing clinical research sites, obtaining biologic reagents, organizing correlative laboratory studies, arranging for storage of patient samples, and procuring other resources as required by the clinical protocols. The NMDP is responsible for placing Requests for Proposals (RFPs) or Requests for Quotations (RFQs), negotiating pricing, terms and conditions, and for placing contracts or purchase orders for the procurement of goods and services for the RCI BMT. The NMDP will follow applicable procurement requirements, such as 45 CFR through CFR states that All procurement transactions shall be conducted in a manner to provide to the maximum extent practical, open and free competition. This regulation shall be implemented as follows: Full and open competition is the preferred method of procurement. The NMDP shall develop, issue, and manage RFPs/RFQs on a competitive basis unless there is an appropriate justification for using other than full and open competition. 3-7

31 The Protocol Chair or his/her designee shall provide assistance with identifying potential suppliers, developing the statement of work, selecting experts to serve on the proposal review committee and establishing the technical review criteria. Persons involved in the procurement process shall not disclose any information about the procurement to prospective offerors unless such disclosure is authorized by the NMDP Contracts Department. Under certain circumstances, using other than full and open competition (e.g., limited competition or sole source awards) may be appropriate. Circumstances that may justify the use of other than full and open competition include: (a) the availability of only one or a limited number of qualified sources; (b) unusual and compelling urgency; and (c) the need to maintain an adequate base of suppliers. To justify the use of other than full and open competition, the Protocol Chair or his/her designee must complete the Selected/Sole Source Justification form and forward the completed form to the NMDP. The NMDP will review the justification and process in accordance with NMDP s procurement policies and procedures. In the circumstance of choosing a select/sole source, the NMDP generally will require that offerors submit detailed cost or pricing information from offerors Trial Initiation Preparation Activities Once the working draft protocol is available and circulated to the Protocol Team, the CIBMTR Trial Initiation and Accrual Specialist begins development of study-related site and patient educational materials. This may include working with NMDP departments; e.g. Office of Patient Advocacy, Search and Transplant Services. The Specialist interacts with the Protocol Chair, Protocol Officer and Protocol Coordinator for review of the draft educational materials. As required, the Accrual Coordinator will prepare: A description of the study to be made available in brochure form and posted on the CIBMTR RCI BMT website (and other appropriate websites) Advertisements for study participant recruitment Web postings for study participant recruitment A series of frequently asked questions (FAQs) for patients and for sites Responses for the RCI BMT staff to use when addressing queries regarding the study as it is publicized Trial overview materials for use by sites to inform and train All study participant education materials and advertisements will be submitted to the NMDP IRB and circulated to study sites with the final approved Protocol Document for submission to their local IRBs Identification of Extra-Network Services The Protocol Chair, Protocol Officer and Protocol Coordinator will review a list of all study participant care measures and investigations that are included in the protocol to determine which, if any, aspects of the protocol will require contracting with service providers outside of the CIBMTR RCI BMT. Examples include: Centralized pharmacy for shipping non-fda approved medications 3-8

32 Research or other central laboratories Radiation quality control services The Protocol Coordinator will provide a list of required extra services to the RCI BMT Director and the CIBMTR Chief Scientific Director. The CIBMTR will identify the provider of choice from the NMDP database of suppliers and, if of a novel nature, will work with the Protocol Chair and Protocol Officer to identify suitable potential providers. This information will be provided to the CIBMTR Financial Officer for initiation of pricing discussions, preparation of a Request for Proposals, if necessary, subcontract discussions and budgeting Addressing Regulatory Requirements The Protocol Chair, Protocol Coordinator and the Protocol Officer will be responsible for addressing regulatory requirements. The Protocol Coordinator will be responsible for: Working with the NMDP Regulatory department to identify any regulatory requirements specific to the protocol (e.g. IND or IDE requirements) Addressing any regulatory requirements once the protocol is sufficiently developed to allow submission to appropriate regulatory authorities Coordinating the submission process with the industry sponsor The Protocol Officer and Protocol Chair will be responsible for: Working with the Protocol Coordinator to identify any regulatory requirements specific to the protocol (e.g. IND or IDE requirements) Ensuring an IND/IDE application is completed if necessary 3.9. Site Identification Once the Working Draft Protocol is available, the Protocol Officer will determine whether any additional CIBMTR centers should be added to the roster of participating centers. This determination will be based on the study sample size, study participant population and type of transplant. If additional sites are required, the Protocol Officer and Protocol Chair will work with a CIBMTR master s level statistician to identify additional centers that have the appropriate patient population and transplant capabilities to be considered for participation in the trial. The Protocol Officer will provide a brief summary of the centers eligible for participation to the Protocol Coordinator who will send an announcement to the identified CIBMTR Transplant Center Directors with an invitation to participate. The Protocol Coordinator will send to each potential site a Site Information sheet for completion. A final decision regarding the need for additional center participation will be made by the Protocol Team once the Final Draft Protocol is submitted to the DSMB for review. To initiate subcontracting discussions, the Protocol Coordinator will submit a list of participating centers to the CIBMTR Financial Officer. Additional criteria given consideration for choosing transplant centers for participation will include prior accrual history and retention rates to other RCI BMT or BMT CTN studies and the need for special training for study-specific procedures (e.g., graft manipulation). The Protocol Coordinator will post a list of all final participating centers on the CIBMTR website. 3-9

33 3.10. Protocol Specific Site Training During the development of the draft Protocol, the Protocol Coordinator and Protocol Officer will identify Study Site training requirements for a specific study. This may be necessary for patient evaluations (e.g., grading GVHD), use of a new device (e.g., graft manipulation), or web-based CRF completion. For areas requiring special training, the Protocol Coordinator will identify appropriate individuals to conduct the training. If related to a particular device, the manufacturer of the device will be considered as a potential source of training personnel. For web-based data collection issues, the Protocol Coordinator or designee will conduct the necessary training. When such training requires contracting with outside organizations, the name, contact information and required activity will be forwarded to the NMDP Financial Officer who will initiate subcontract discussions with the potential provider. In addition, the NMDP Financial Officer will use this information when determining the study budget. See additional information regarding training in Chapter Ancillary Studies Definition An ancillary study entails the collection from study participants of data and/or specimens, or the conduct of additional analyses of existing materials or samples that are outside the specific objectives of the primary study. Ancillary studies may also be characterized by: Requiring a separate consent form Placing an additional burden on participants Being funded by a separate funding mechanism or source Process for Initiation and Approval Proposals for ancillary studies must be presented in writing, using standard RCI BMT Proposal format, to the Protocol Team for review and approval. An important factor in review of ancillary study protocols is the determination that the objectives and implementation of the primary study are not compromised. If approved by the Protocol Team, the ancillary study concept will be presented to the CTAC for review and approval. Ancillary studies can be divided into two major categories: 1. Those that do not require a separate consent and entail no additional participant burden. They require notification of the DSMB if the study is approved for implementation and/or funding identified. Note that review/approval by the DSMB is not required prior to implementation or funding. 2. Those that require a separate consent and/or cause additional participant burden. After CTAC approval and identification of funding, the study will be sent to the DSMB for approval. The role of the DSMB is to ensure participant safety and not scientific merit. Approval by the DSMB must be obtained prior to implementation. 3-10