resource for clinical investigation in blood and marrow ... _mop.pdf · final draft.....3-4 3.2.4....

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 55413-5000 USA

(612) 884-8660

Medical College of Wisconsin P.O. Box 26509 8701 Watertown Plank Road Milwaukee, WI 53226 USA (414) 456-8325

www.cibmtr.org

TTHHIISS PPAAGGEE LLEEFFTT IINNTTEENNTTIIOONNAALLLLYY BBLLAANNKK

CIBMTR Administrative MOP

TABLE OF CONTENTS

1. ORGANIZATION .........................................................................................................1-1

1.1. Mission Statement and Organizational Overview ......................................................1-1

1.2. RCI BMT Clinical Trials Office ...................................................................................1-2

1.3. RCI BMT Office Clinical Trials Staff..........................................................................1-3

1.4. Trial Centers...................................................................................................................1-4

1.5. Clinical Trial Advisory Committee (CTAC) ...............................................................1-4

1.6. Study Administration ....................................................................................................1-4 1.6.1. Protocol Team ............................................................................................................. 1-4 1.6.2. Data and Safety Monitoring Board (DSMB) .............................................................. 1-4 1.6.2.1. Purpose ...................................................................................................................1-4 1.6.3. Central Institutional Review Board (IRB) .................................................................. 1-5 1.6.4. Guidelines for Reporting Adverse Events to Institutional Review Boards................. 1-5

2. STUDY CONCEPT DEVELOPMENT AND APPROVAL ......................................2-1

2.1. Developing a Proposed Study Concept ........................................................................2-1

2.2. Contents of a Study Concept.........................................................................................2-1

2.3. Proposal Review.............................................................................................................2-2 2.3.1. Review Packet............................................................................................................. 2-2 2.3.2. Review of the Study Concept by the Clinical Trials Advisory Committee (CTAC).. 2-2 2.3.3. Review of CTAC approved proposals by the CTO .................................................... 2-3

2.4. Review Cycle...................................................................................................................2-3

3. PROCEDURES FOR IMPLEMENTING APPROVED STUDY CONCEPTS ......3-1

3.1. Tasks Following Approval of a Study Concept...........................................................3-1 3.1.1. Establishment of a Protocol Team .............................................................................. 3-1

3.2. Development of a Protocol ............................................................................................3-3 3.2.1. Primary Draft .............................................................................................................. 3-3 3.2.2. Working Draft ............................................................................................................. 3-3 3.2.3. Final Draft ................................................................................................................... 3-4 3.2.4. DSMB Review ............................................................................................................ 3-4

3.3. Development of Case Report Forms (CRFs) and Study Database............................3-4

3.4. Study Budget Preparation, Management of Contributions and Procurement Guidelines..............................................................................................................3-5

3.4.1. Study Budget Preparation and Revisions.................................................................... 3-5 3.4.2. Procurement Guidelines .............................................................................................. 3-5 3.4.3. Management of Contributions..................................................................................... 3-5 3.4.4. Protocol Specific Costs ............................................................................................... 3-5 3.4.5. Travel .......................................................................................................................... 3-6 3.4.6. Contributions............................................................................................................... 3-6 3.4.7. Budget Review Process............................................................................................... 3-7

i


3.4.8. Expenses...................................................................................................................... 3-7 3.4.9. Budget Revisions ........................................................................................................ 3-7 3.4.10. Protocol Amendments................................................................................................. 3-7

3.5. Procurement Guidelines for RCI BMT Office............................................................3-7

3.6. Trial Initiation Preparation Activities .........................................................................3-8

3.7. Identification of Extra-Network Services ....................................................................3-8

3.8. Addressing Regulatory Requirements .........................................................................3-9

3.9. Site Identification...........................................................................................................3-9

3.10. Protocol Specific Site Training ...................................................................................3-10

3.11. Ancillary Studies ..........................................................................................................3-10 3.11.1. Definition .................................................................................................................. 3-10 3.11.2. Process for Initiation and Approval .......................................................................... 3-10 3.11.3. Funding for Ancillary Studies................................................................................... 3-11 3.11.4. Ancillary Study Monitoring ...................................................................................... 3-11 3.11.5. Manuscript Approval and Publication ...................................................................... 3-11 3.11.6. Data Analysis and Publication Issues ....................................................................... 3-11

4. PROCEDURES FOR APPROVAL OF PROTOCOL AMENDMENTS.................4-1

4.1. Proposal of a Protocol Amendment..............................................................................4-1

4.2. Review of Proposal for Protocol Amendment .............................................................4-1

4.3. Finalizing the Protocol Amendment.............................................................................4-2

4.4. Regulatory Authorities and Documents.......................................................................4-2

4.5. Case Report Form (CRF) Revisions.............................................................................4-2

4.6. Protocol Budget Revisions.............................................................................................4-3

4.7. Extra Services Revisions................................................................................................4-3

4.8. Initiation and Accrual Activity Revisions....................................................................4-3

4.9. Additional Site Training................................................................................................4-3

5. SITE MONITORING....................................................................................................5-1

5.1. Initiation Site Visits........................................................................................................5-1 5.1.1. Follow-up Monitoring Visits ...................................................................................... 5-1

5.2. Data Quality Assurance.................................................................................................5-2 5.2.1. Data Editing ................................................................................................................ 5-2 5.2.2. Missing Forms............................................................................................................. 5-2

5.3. Evaluation of Center Performance...............................................................................5-2

6. ADVERSE EVENT REPORTING ..............................................................................6-1

6.1. Definition of Adverse Event ..........................................................................................6-1 6.1.1. Adverse Event Definitions .......................................................................................... 6-1

6.2. Unexpected Adverse Events ..........................................................................................6-2

ii


6.3. Expected Adverse Events ..............................................................................................6-3

6.4. Monitoring Adverse Events ..........................................................................................6-3

6.5. Adverse Event Reporting and Management ...............................................................6-6 6.5.1. FDA IND/IDE Reporting............................................................................................ 6-6 6.5.2. Monitoring Toxicity .................................................................................................... 6-7

6.6. Guidelines for Reporting Adverse Events to Institutional Review Boards ..............6-7 6.6.1. Adverse Event Documentation ................................................................................... 6-7 6.6.2. Providing Follow-up Information to Local IRBs........................................................ 6-8 6.6.2.1. Early Phase Multi-Center Clinical Trials ...............................................................6-8 6.6.3. Requests from an IRB for Additional Information ..................................................... 6-8

7. HUMAN SUBJECT PROTECTION AND REGULATORY PROCEDURES .......7-1

7.1. Institutional Review Board ...........................................................................................7-1

7.2. Health Insurance Portability and Accountability Act (HIPAA) ...............................7-1

7.3. Office of Human Research Protections (OHRP) Institutional Assurances ..............7-1

7.4. Participation of Women, Ethnic Minorities and Children.........................................7-1

7.5. Site Regulatory Documents...........................................................................................7-1

7.6. Investigational New Drug or Investigational Device Exemption Application..........7-2

8. PUBLICATIONS, PRESENTATIONS, ABSTRACTS, DATA REQUESTS AND SAMPLE REQUESTS...................................................................................................8-1

8.1. Guidelines .......................................................................................................................8-1

8.2. Amendments to Guidelines ...........................................................................................8-1

8.3. Continuing Review Regarding Formal Presentation of Data and the Assignment of Writing Teams ......................................................................................................8-1

8.4. Policy Regarding Oral Presentation of RCI BMT Related Data ..............................8-1

8.5. General Policy ................................................................................................................8-1 8.5.1. Approvals and Submission.......................................................................................... 8-2 8.5.2. Manuscript Requirements ........................................................................................... 8-2 8.5.2.1. Titles.......................................................................................................................8-2 8.5.2.2. Acknowledgments ..................................................................................................8-2

8.6. Manuscripts Describing Data from CIBMTR RCI BMT Trials...............................8-2 8.6.1. Data Analysis .............................................................................................................. 8-2 8.6.2. Writing Responsibilities.............................................................................................. 8-2 8.6.3. Acknowledgement of Donations and Other Protocol Support.................................... 8-3 8.6.3.1. Donations ...............................................................................................................8-3 8.6.3.2. Data and Publications.............................................................................................8-3 8.6.4. Attributions ................................................................................................................. 8-3 8.6.5. Timelines..................................................................................................................... 8-3

8.7. Authorship ......................................................................................................................8-3 8.7.1. Authorship Eligibility Requirements .......................................................................... 8-4 8.7.2. Establishing the Order of Authors .............................................................................. 8-4

iii


8.7.3. Removing Authors ...................................................................................................... 8-4 8.7.4. Authorship on Joint Studies ........................................................................................ 8-4

8.8. Abstracts, Public Presentations, Electronic Postings .................................................8-4 8.8.1. General ........................................................................................................................ 8-4 8.8.2. Abstracts...................................................................................................................... 8-4 8.8.3. Public Presentations and Electronic Postings of Study Data ...................................... 8-5

8.9. Ancillary Studies, Laboratory Studies, Position Papers and Technical Reports.....8-5 8.9.1. General ........................................................................................................................ 8-5

8.10. Data Requests .................................................................................................................8-5 8.10.1. Types of Data Available ............................................................................................. 8-5 8.10.2. Stipulations for Data Requests .................................................................................... 8-5 8.10.3. Requesting Data .......................................................................................................... 8-6 8.10.3.1. Access to Data and Classification of Data .............................................................8-6 8.10.3.2. Types of Data Requests..........................................................................................8-6

8.11. Sample Requests.............................................................................................................8-6 8.11.1. Types of Samples Available........................................................................................ 8-7 8.11.2. Overview of the Request Process................................................................................ 8-7 8.11.3. Requesting Samples .................................................................................................... 8-7 8.11.3.1. Access to Samples ..................................................................................................8-7 8.11.3.2. Restrictions.............................................................................................................8-7 8.11.3.3. Disclaimer ..............................................................................................................8-8 8.11.3.4. Acknowledgements ................................................................................................8-8 8.11.4. How Requests Are Reviewed/Approved for Samples and Corresponding Data ........ 8-8 8.11.5. How Samples Are Distributed to Requestor ............................................................... 8-8

8.12. Definitions.......................................................................................................................8-8 8.12.1. Journal Articles ........................................................................................................... 8-8 8.12.2. Presentations ............................................................................................................... 8-8 8.12.3. Electronic Media ......................................................................................................... 8-9

9. CIBMTR RCI BMT SHIPPING INSTRUCTIONS USING FEDERAL EXPRESS........................................................................................................................9-1

APPENDIX A Clinical Trials Advisory Committee Charter

APPENDIX B Data Safety Monitoring Board Charter

APPENDIX C Study Proposal Application and Template

APPENDIX D Financial Disclosure Example

iv


CCHHAAPPTTEERR 11

RRCCII BBMMTT OORRGGAANNIIZZAATTIIOONN


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 Figure 1.11.1 CIBMTR Organizational StructureCIBMTR Organizational Structure

AdvisoryCommittee

ExecutiveCommittee

Working/SteeringCommittees

Immunobiology Clinical TrialsSupport

ObservationalResearch

Clinical Outcomes Health Policy

StatisticalMethodology

OrgCht07_29.ppt

Assembly

SeniorResearchAdvisor

MCW –IBMTR

NMDP –Research

BMT CTN*

Chief Scientific DirectorChief Statistical Director

RCI BMT

* = The BMT CTN Data and Coordinating Center is a Collaboration of CIBMTR, NMDP and the EMMES Corporation

Joint AffiliationCommittee

Executive Director

Consumer Advocacy CommitteeInternational Studies Committee

NominatingCommittee

1-1


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 CIBMTR Assistant Scientific Director and Program Director for the RCI BMT

Mary Horowitz, MD, MS CIBMTR Chief Scientific Director

Daniel Weisdorf, MD CIBMTR Senior Advisor

Dennis Confer, MD NMDP Chief Medical Officer

Mary Eapen, MD, MS CIBMTR Assistant Scientific Director

Rebecca Drexler, BS CIBMTR Minneapolis Program Manager

Brent Logan, PhD CIBMTR PhD Statistician

Gordy Bryan NMDP and CIBMTR Chief Financial Officer

The functions of the CTO include:

Develop and maintain a Manual of Procedures

Ratify major changes in the Manual of Procedures

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


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.

1.3. 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


- 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).

1.6. 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.

1.6.1. 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

1.6.2. Data and Safety Monitoring Board (DSMB)

1.6.2.1. 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


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).

1.6.3. 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.

1.6.4. 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


1-6



1-7


CCHHAAPPTTEERR 22

SSTTUUDDYY CCOONNCCEEPPTT DDEEVVEELLOOPPMMEENNTT AANNDD AAPPPPRROOVVAALL


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.

2.2. 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, e-mail)

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


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.

2.3. Proposal Review

2.3.1. 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.

2.3.2. 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 1.00-5.00 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


2.3.3. 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.

2.4. 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



2-4


CCHHAAPPTTEERR 33

PPRROOCCEEDDUURREESS FFOORR IIMMPPLLEEMMEENNTTIINNGG AAPPPPRROOVVEEDD SSTTUUDDYY CCOONNCCEEPPTTSS


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

3.1.1. 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


- 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


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.

3.2. 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.

3.2.1. 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).

3.2.2. 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 email 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 email. 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


central IRB submission. If necessary, an updated document of the Final Approval by the protocol team will be obtained after DSMB recommendations.

3.2.3. 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

3.2.4. 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.

3.3. 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


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 3.4.1. 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.

3.4.2. 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.

3.4.3. 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”

3.4.4. 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 $2000.00 per center and shall include:

3-5


- 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 non-standard 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.

3.4.5. 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.

3.4.6. 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


3.4.7. 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.

3.4.8. Expenses

The NMDP shall track and reconcile the RCI BMT Office protocol-related funds, make payments to suppliers and reconcile all costs quarterly.

3.4.9. 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 re-approved. If additional funds are not committed, the budget must be rerouted for approval for any additional projected expenditures.

3.4.10. 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.

3.5. 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 74.40 through 74.48. 45 CFR 74.43 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


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.

3.6. 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.

3.7. 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


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.

3.8. 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


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 5.

3.11. Ancillary Studies

3.11.1. 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

3.11.2. 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


3.11.3. Funding for Ancillary Studies

Funding for ancillary studies may be from the investigator’s institution, private sources, or the NIH. Funding for ancillary studies is not supplied by the CIBMTR RCI BMT. If needed, the funding application may include a copy of the CTAC approval and the DSMB approval if applicable.

3.11.4. Ancillary Study Monitoring

Ancillary study data will be monitored by the DSMB if the ancillary study is classified in category 2 above. If the monitoring of an ancillary study requires additional expertise beyond that represented by the standing DSMB membership, consideration may be given to adding ad hoc members.

3.11.5. Manuscript Approval and Publication

The Protocol Team and CIBMTR CTO of the RCI BMT must approve all manuscripts, presentations or abstracts from an ancillary study prior to submission. Manuscripts must be provided to the CIBMTR CTO prior to submission to a journal for review.

The Protocol Team and the CIBMTR CTO should verify that the primary protocol will not be jeopardized by publications from an ancillary study.

3.11.6. Data Analysis and Publication Issues

Ancillary study investigators should discuss policies concerning publications and ownership of data with the Protocol Team before initiation of an ancillary study. The Protocol Team and ancillary study investigators should determine study management requirements. The Protocol Team and ancillary study investigator should address the following issues:

• Releasing limited data from the main study to the ancillary study investigators

• Timing of publication of an ancillary study with respect to publication of results of main study

• The Health Insurance Portability and Accountability Act (HIPAA) requirements concerning the sharing of data between Protocol Team and ancillary study investigators. The DSMB should indicate in their review if they believe that the HIPAA requirements pose too great a barrier to the accomplishment of an ancillary study.

Unless proprietary information is involved, ancillary study investigators are expected to provide their data to the CIBMTR so that the ancillary study data can be linked to the main study data. The transfer of ancillary study data will be determined on a case-by-case basis by the Protocol Team, ancillary study Principal Investigator and the CTO.

3-11



3-12


CCHHAAPPTTEERR 44

PPRROOCCEEDDUURREESS FFOORR AAPPPPRROOVVAALL OOFF PPRROOTTOOCCOOLL AAMMEENNDDMMEENNTTSS


4. PROCEDURES FOR APPROVAL OF PROTOCOL AMENDMENTS

Approved protocols may require amendments to address issues that arise during study conduct or to reflect new information that arises from other studies that affect the conduct of an ongoing study. This chapter defines the steps for preparing amendments for approved and/or active protocols.

4.1. Proposal of a Protocol Amendment

Proposals for protocol amendments may come from participating centers, the Protocol Team, or the DSMB. All proposals should be submitted to the Protocol Coordinator.

The Protocol Coordinator is responsible for:

Recording the requested modification.

Contacting the submitting individual for any clarification.

Distributing the proposed amendment to the Protocol Officer and if applicable, the Protocol Team.

Assigning a protocol version number.

Maintaining a list of version numbers and copies of amendment and review documents. If necessary, the Protocol Officer may contact the submitting individual to further discuss and clarify the proposed amendment. Changes recommended by the DSMB should be discussed with the CIBMTR RCI BMT Director and/or the CIBMTR Chief Scientific Director.

4.2. Review of Proposal for Protocol Amendment For amendments recommended by the DSMB, the Protocol Officer will review the proposed amendment and the rationale and may discuss the changes with the Protocol Chair(s), Protocol Team (if necessary), and the RCI BMT Director. The Protocol Team will prepare a response to the DSMB recommendations. For other amendments, the Protocol Officer will review the proposed amendment and the rationale and discuss the changes with the Protocol Chair(s). A decision regarding the need for a protocol amendment is the responsibility of the Protocol Officer in consultation with the Protocol Chair and Protocol Team. If there is a disagreement regarding the protocol amendment, the CTO will review the justification and rationale for the amendment and arbitrate. The decision of the CTO whether to proceed with a protocol amendment is binding. The RCI BMT Director may consult with other members of the CIBMTR or outside experts, as required, prior to reaching a decision. The Protocol Officer is responsible for:

Collaborating with the Protocol Chair and Protocol Statistician to draft the protocol amendment.

Contacting the Protocol Coordinator to send notification to the participating centers that a protocol amendment is pending.

4-1


4.3. Finalizing the Protocol Amendment

All protocol amendments must be reviewed and accepted by members of the DSMB. The review may take place at a DSMB meeting, on a conference call, or by ballot. It is recommended, that members of the DSMB review amendments that impact study design, enrollment, or patient safety prior to distribution to study centers ad hoc. Other types of amendments may be held for review until a DSMB meeting or conference call. The Protocol Officer and/or Protocol Coordinator will determine the appropriate review process in collaboration with the RCI BMT Director. Amendments distributed to the DSMB for review should include the following:

A protocol amendment cover letter stating the old and new version numbers.

A summary of protocol changes with changes documented and highlighted. A revised protocol with changes highlighted may also be included.

Once amendments are approved by the DSMB they must be submitted to the NMDP IRB for approval prior to disseminating to participating sites. Participating centers will be notified of protocol amendments by an e-mail announcement from the RCI BMT. Amendment documents may be included with the e-mail announcement and will be posted on the CIBMTR RCI BMT website. The documents will include:

A protocol amendment cover letter stating the old and new version numbers.

A revised protocol amendment including a summary of protocol changes, a revised protocol with changes highlighted, and a second version with the changes fully incorporated into the document.

4.4. Regulatory Authorities and Documents

Participating centers are required to submit all protocol amendments to their IRB for approval. After receiving approval from its IRB, each center must submit the IRB approval letter for the protocol amendment to the Protocol Coordinator. After receiving IRB approvals, the Protocol Coordinator is responsible for:

Recording the protocol amendment approvals from each participating center.

Notifying the appropriate regulatory authorities (if there is an IDE or IND, the FDA) of the protocol amendment approvals.

Forwarding a copy of the revised protocol document to the appropriate regulatory authorities.

4.5. Case Report Form (CRF) Revisions

CRFs and the study database may need to be modified as a result of a protocol amendment. The Protocol Coordinator takes the following steps regarding case report form and/or study database revisions:

Review the final amendment to determine if any changes are required.

Draft changes to the CRFs.

Review changes with the EMMES Project Officer or Protocol Statistician.

4-2


Implement changes and coordinate a software release with the project programmer.

4.6. Protocol Budget Revisions 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 are forwarded to the RCI BMT Director. The CIBMTR Financial Officer revises the budget and participating centers’ payment schedule accordingly. After review by the Protocol Officer, the CIBMTR Financial Officer forwards the revised budget to the Protocol Coordinator for filing and for circulation to the Protocol Chair, CTO, and all participating centers.

4.7. Extra Services Revisions The Protocol Officer, Protocol Chair and Protocol Coordinator are responsible for reviewing the amendment to determine if any changes that have been made affect the use of extra services. If changes are required, the nature of the changes is forwarded to the RCI BMT Director who:

Communicates with NMDP Contracts Officer and the extra providers and renegotiates subcontracts as required.

Addresses the changes and revises the budget accordingly.

Forwards a copy of any revised contracts to the Protocol Coordinator for filing and for circulation to the Protocol Chair and Protocol Officer.

4.8. Initiation and Accrual Activity Revisions

The Protocol Coordinator and Protocol Officer review the protocol amendment to determine if any changes are required to the patient information documents, study postings or FAQs that are being used by the CIBMTR Initiation and Accrual Specialist. If required, the nature of the changes is reviewed with the CIBMTR Initation and Accrual Specialist. The Specialist will coordinate any required changes and, if necessary, the Protocol Coordinator and Protocol Officer will review any revised information or documents prior to their implementation.

4.9. Additional Site Training The Protocol Coordinator reviews the protocol amendment to determine whether any additional center training is required. If additional training requirements are identified, 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. When such training requires contracting with outside organizations, the name, contact information and required activity will be forwarded to the RCI BMT Director who will initiate subcontract discussions with the potential provider and determine the study budget. The CIBMTR and EMMES Project Officer are responsible for all training involving form completion and submission issues.

4-3



4-4


CCHHAAPPTTEERR 55

SSIITTEE MMOONNIITTOORRIINNGG


5. SITE MONITORING

As part of the Quality Assurance plan, monitoring will be a continuous, ongoing and multifaceted process. This includes external review by the DSMB and IRBs, as well as internal data quality control, review and evaluation. Site monitoring visits are central to this process, and will include reporting to appropriate individuals with oversight responsibilities.

5.1. Initiation Site Visits Prior to study initiation, each clinical site and laboratory will be assessed either in person or remotely to ensure each facility possesses the following:

Adequate facilities and equipment to conduct the studies

Site personnel adequately knowledgeable and trained in protocol(s) requirements, study policies, procedures and the data entry system

Adequate processes are established to protect the rights and safety of all study participants involved in the protocol

Designated monitor(s) will contact each clinical site to evaluate the pharmacy and clinical unit, patient record storage area, and computer facilities. Contacting the centers is also used to ensure that adequate communication among all center staff is in place. Subsequent to the start of any study, all clinical sites will also be evaluated following these same procedures. Laboratories will also be evaluated to confirm that the laboratory possesses the necessary professional certifications and licenses, and that laboratory operations quality assurance programs, assays, equipment and staff meet study requirements.

5.1.1. Follow-up Monitoring Visits

The CIBMTR will conduct monitoring visits periodically at the participating centers and laboratories. The visits are conducted by one or more designated protocol coordinators and may be accompanied, as appropriate, by other CIBMTR RCI BMT representatives. The purpose of the site visit is to conduct a data audit to ensure compliance with protocol requirements, regulatory requirements, and study policies and procedures. These visits are also used to exchange information regarding protocol adherence, review clinic, laboratory and pharmacy operations, provide training, check drug accountability, assess compliance with IRB reporting procedures for serious adverse events and discuss any problems encountered with regard to implementation or compliance with the protocol design. In addition, an overall assessment of management, coordination, and communications of the study site is conducted. Consequently, information can be easily exchanged, mutual problems can be resolved and study quality can be maximized. Site visits occur at variable frequency throughout the course of the study, depending primarily upon the stage of the study, site performance, and sponsoring agency requirements. Activities include those required to enhance data quality, ensure study integrity, satisfy regulatory requirements, and evaluate site performance. An agenda for this site visit will be provided to the Principal Investigator at least two weeks in advance of the visit.

5-1


The site monitor team will hold a summary meeting following the completion of agenda with the Principal Investigator, the Lead Investigator and Clinical Research Associate to discuss the team’s observations, review any problems identified, and provide a preliminary report of the visit to the site. A formal written report of the site visit is to be prepared by the CIBMTR RCI BMT and distributed in a timely manner. If site-specific problems of a serious nature are identified (e.g., failure to obtain informed consent, failure to have enrolled study participants sign the most current IRB-approved Informed Consent, enrollment of ineligible study participants, pharmacy or product administration errors), appropriate steps will be taken as detailed below.

5.2. Data Quality Assurance Database quality will be maintained through a variety of analyses that target anomalies, delinquent data and key entry errors. Reports summarizing anomalies found are transmitted to the transplant centers for resolution. A part of this process will be to analyze the frequency of errors according to type to determine if certain types of errors are recurrent. Modifications to the data entry system will be made if the errors occur frequently across transplant centers. If errors are localized within a transplant center, steps will be taken to resolve the problems by additional training to the center or modifications to the data system. The Protocol Coordinator or Clinical Research Specialist is expected to carefully check all data for completeness and consistency. Numerical values, such as hemotological values will be cross-checked by computer to ensure accuracy. Validation may be required from the site to verify data. This is further elaborated upon in Chapter 9.

5.2.1. Data Editing

Data editing at the CIBMTR RCI BMT involves reviewing data forms received from the sites for completeness, internal consistency, protocol compliance and adherence to the MOP. At minimum on a quarterly basis, computer generated queries will be posted for each center. The queries will identify incomplete, questionable, or inconsistent data. Each center must either correct the data in the CRFs or provide an explanation on the validity of the existing data.

5.2.2. Missing Forms

The determination of missing or delinquent data will be performed at both a form and field level. Delinquent forms will be identified and compared to an exception list. All missing forms will be identified by form type for each study participant enrolled in a protocol. The Internet data entry system, AdvantageEDCSM, will provide a table that summarizes all forms submitted and past due forms listed by study participant. After a form is entered, the list of forms submitted and outstanding forms is updated. A missing form will continue to be requested until the form is transmitted or until an exception is granted and entered into the missing forms exception file. Protocol Coordinator or Clinical Research Specialist is required to review these tables for all study participants on a frequent basis.

5.3. Evaluation of Center Performance The success of multi-center trials depends on high quality performance from the participating sites and careful coordination of effort. It will be the responsibility of the CIBMTR RCI BMT to provide analyses and periodic reports on site performance with oversight from the CTAC. The

5-2


CIBMTR RCI BMT is responsible for conducting site-monitoring visits and for the administrative and statistical aspects of site evaluation. For the evaluation process to be successful, it is important to maintain open lines of communication among all parties, periodically review the common goals in order to maintain the highest degree of study integrity and ensure protection of human study participants within an environment that strives for continuous improvement of processes and operations. Monthly accrual reports for each protocol will be prepared by the CIBMTR RCI BMT, posted on the private RCI BMT website and presented to the CTAC. Centers not meeting accrual goals will be contacted by the, RCI BMT Director, the Protocol Officer, the Protocol Chair and/or the CTAC Chair to determine the cause of slow accrual and if any corrective processes would improve accrual. The CIBMTR Initiation and Accrual Specialist will work with the Protocol Officer and Coordinator to develop and execute a plan to address slow accrual. Summaries of missing forms and days past due, by center, will be provided to the DSMB at each meeting. The RCI BMT CTO will contact centers with serious delinquencies to resolve any training or staffing issues. After each data audit, the error rate by center will also be provided to the DSMB for review. Periodic reports of center performance will be supplied to the Protocol Chair and the DSMB. Serious violations, such as failure to obtain informed consent, enrollment of ineligible study participants, treatment or pharmacy errors, etc. however, will result in prompt notification to the CTO. The RCI BMT will analyze each serious violation to determine the impact of the error on study integrity. The issue will be discussed with the center and the center PI will be responsible for supplying a written explanation of the violation and corrective action taken. Remote Monitoring Activity In addition to site visits, the RCI BMT routinely monitors accrual reports, CRFs, missing forms and responses to queries. The Protocol Coordinator has responsibility for identifying sites with problems in these areas and referring them to the Protocol Chair and Protocol Officer. The Protocol Chair and Protocol Officer will determine whether corrective action is indicated. The corrective action may include, but not be limited to, discussion with the Principal Investigator, additional training of site personnel, a site visit, or referral to the CTO. Final Visit For some studies, it may be appropriate to conduct final closeout visits, which occur after the study is completed and all data and finalized case reports are submitted. During this visit, the monitoring team determines study completion status. The review of regulatory compliance and documentation are done. The RCI BMT Office policy for maintaining records is also reviewed with the site. The return of supplies and/or study medication is also completed. After the visit, a final report, indicating the completion of the study, will be prepared.

5-3



5-4


CCHHAAPPTTEERR 66

AADDVVEERRSSEE EEVVEENNTT RREEPPOORRTTIINNGG


6. ADVERSE EVENT REPORTING

6.1. Definition of Adverse Event An adverse event (AE) is an unplanned, unwanted event which occurs to a study participant and which is possibly related to the use of protocol therapy. While some events may not initially appear to be associated with the use of the study treatment, a relationship may not emerge until sufficient numbers of reports accumulate from various Transplant Centers. It is CIBMTR RCI BMT policy that adverse events must be reported even if the investigator is unsure whether a relationship exists between the adverse event and the use of the study treatment.

6.1.1. Adverse Event Definitions

Adverse Event - Any unfavorable and unintended sign (including an abnormal laboratory finding), symptom or disease temporally associated with the use of a medical treatment or procedure regardless of whether it is considered related to the medical treatment or procedure (attribution of definite, probable, possible, unlikely, or unrelated). Life-Threatening Adverse Event - Any adverse event that places the participant, in view of the investigator, at immediate risk of death from the reaction. Serious Adverse Event (SAE) - Any adverse event that results in any of the following outcomes: death, a life threatening adverse event, in-patient hospitalization or prolongation of existing hospitalization, a persistent or significant disability/incapacity, or a congenital anomaly/birth defect. Unexpected Adverse Event - Any adverse event, the specificity or severity of which is NOT listed in the study protocol, product inserts or informed consent document. Attribution - The determination of whether an adverse event is related to a medical treatment or procedure. Attribution categories:

Definite The adverse event is clearly related to the study drug/device/procedure/ treatment(s).

Probable The adverse event is likely related to the study drug/device/procedure/

treatment.

For CIBMTR RCI BMT studies: the adverse event is not likely to be caused by the subject’s underlying medical condition or other concomitant therapy, and the nature of the adverse event or the temporal relationship between the onset of the adverse event and study drug/device/treatment administration lead the investigator to believe that there is a reasonable chance of causal relationship.

6-1


Possible The adverse event may be related to the study drug/device/procedure/ treatment(s).

For CIBMTR RCI BMT studies: the adverse event could be attributed to the subject’s underlying medical condition or other concomitant therapy, but the nature of the adverse event or the temporal relationship between the onset of the adverse event and study drug/device/treatment administration lead the investigator to believe that there could be a causal relationship.

Unlikely The adverse event is doubtfully related to the study drug/device/

procedure/treatment(s).

Unrelated The adverse event is clearly NOT related to the study drug/device/procedure/ treatment(s).

For CIBMTR RCI BMT studies: the adverse event is most plausibly explained by the subject’s underlying medical condition or other concomitant therapy, or the adverse event has no plausible biological relationship to study drug/device /treatment.

Common Terminology Criteria Adverse Events (CTCAE) – a descriptive terminology developed by the National Cancer Institute (NCI) for use in reporting adverse events. The CTCAE includes a grading (severity) scale for each adverse event term. An appendix for grading BMT-related complex/ multi-component events is included. A copy of the current CTCAE guidelines (Version 3.0) is located at http://ctep.cancer.gov/reporting/. Grade – Severity of the adverse event. Grades were developed using the following guidelines: Grade 0 – No adverse event or within normal limits 1 – Mild adverse event 2 – Moderate adverse event 3 – Severe adverse event 4 – Life-threatening or disabling adverse event 5 – Fatal adverse event

6.2. Unexpected Adverse Events Exhibit 6-1-1 provides unexpected adverse event reporting requirements for study centers participating in a CIBMTR RCI BMT study. Adverse events should be reported using CTCAE terminology and severity scales. Reporting requirements are calibrated to the severity of the event and the perceived relationship of the event to the study drug/device/treatment. All Grade 3-5 unexpected adverse events must be reported to the CIBMTR RCI BMT Coordinating Center in an expedited manner irrespective of the attribution of the event to the study drug/device/procedure/treatment.

6-2


In general, investigators should report adverse events as diseases or syndromes whenever possible, instead of reporting individual component symptoms, signs, laboratory abnormalities, and sequelae.

6.3. Expected Adverse Events Exhibit 6-1-2 provides expected adverse event reporting requirements for study centers participating in a CIBMTR RCI BMT study. Adverse events should be reported using CTCAE terminology and severity scales. All fatal (Grade 5) expected adverse events will be reported in an expedited manner to the RCI BMT Coordinating Center. Most protocol-specific life-threatening or disabling (Grade 4) and other non-fatal expected adverse events will be reported on study forms submitted on a defined forms submission schedule. Grade 4 adverse events not collected on study forms should be reported in an expedited manner. In addition, each protocol team must develop an interim analysis plan to monitor protocol-specific expected adverse events. The plan will be included in the study protocol.

6.4. Monitoring Adverse Events

Unexpected Adverse Events Unexpected adverse events will be reported via a web-based AE system. Protocol Coordinators will review daily all submitted unexpected adverse events and forward the information to the Medical Monitor for review. All unexpected adverse events will be reviewed by the Medical Monitor at, or associated with the RCI BMT, within 2 business days of receiving the summary of the adverse event from the transplant center. If the Medical Monitor requires additional information to make his/her assessment, study centers will have 4 business days to respond to the request for additional information. The Medical Monitor has medical expertise relevant to the study protocol and may request the participant's treatment assignment when reviewing the adverse event. The Medical Monitor or RCI BMT representative is responsible for notifying the CIBMTR Chief Scientific Director or the RCI BMT Director immediately of all Grade 3-5 unexpected adverse events and of any concerns regarding the frequency or type of adverse event(s) on a study or study treatment arm. The CIBMTR Chief Scientific Director or the RCI BMT Director is responsible for reviewing the adverse event materials to determine if the materials are complete. If there are any concerns regarding the type or frequency of the event, the DSMB Executive Secretary will be requested to notify the DSMB Chair. The DSMB Chair will review the adverse event materials, determine if the information is complete, determine if additional DSMB review is required and make recommendations to the CIBMTR RCI BMT concerning continuation of the study. Full documentation of the procedures will be available at the RCI BMT. The RCI BMT will prepare semi-annual summary reports of all unexpected adverse events for the CIBMTR Chief Scientific Director, the RCI BMT Director, and the DSMB Chair. Semi-

6-3


annual reports will be made available on a secure website and the CIBMTR Chief Scientific Director, the RCI BMT Director, and DSMB Chair will be notified by e-mail when the materials are posted. Expected Adverse Events The RCI BMT will prepare semi-annual summary reports of all Grade 5 expected adverse events for the CIBMTR Chief Scientific Director, the RCI BMT Director, and the DSMB Chair. Semi-annual reports will be made available on a secure website and the CIBMTR Chief Scientific Director, the RCI BMT Director, and DSMB Chair will be notified by e-mail when the materials are posted. Grade 3-5 expected adverse events defined in the interim analysis plan will be reported as defined in the protocol. Any concern regarding the type or frequency of a Grade 3-5 expected adverse event will be reported to the CIBMTR Chief Scientific Director or the RCI BMT Director, who will determine if referral to the DSMB is warranted. If required, data materials will be provided by the RCI BMT. The DSMB Executive Secretary will arrange for review by the DSMB Chair. The Chair will determine if additional DSMB review is required and make recommendations to the CIBMTR Chief Scientific Director and the RCI BMT Director concerning continuation of the study. The RCI BMT will ensure that any additional reporting requirements defined by the DSMB Chair and other oversight groups are identified and implemented. The RCI BMT will determine the exact content of these summary reports and the reporting schedule.

6-4


Exhibit 6-1-1

REPORTING UNEXPECTED ADVERSE EVENTS ON CIBMTR RCI BMT STUDIES

SEVERITY GRADE ATTRIBUTION TRANSPLANT CENTER REPORTING REQUIREMENTS

5 - Fatal 4 - Life-threatening or Disabling

All attributions

Submit unexpected adverse event form to the RCI BMT within 24 hours of the event. For Grade 5, also submit study death form to the RCI BMT.

Submit a summary of the adverse event to the RCI BMT within 4 working days. For Grade 5, the summary should include potential contributing causes of death.

Information reported for the adverse event must include: Name of adverse event, date of first onset, peak severity, relationship to study drug/device/treatment, resolution date, actions taken with respect to administration of study drug/device/treatment, and other treatment for the adverse event.

3 – Severe

All attributions Definite Probable Possible Unlikely Unrelated

Submit unexpected adverse event form to the RCI BMT within 3 working days of the adverse event.

Submit a summary of the adverse event to RCI BMT within 4 working days

Information reported for the adverse event must include:

Name of adverse event, date of first onset, peak severity, relationship to study drug/device/treatment, resolution date, actions taken with respect to administration of study drug/device/treatment, and other treatment for the adverse event.

Multiple recurrences of the same adverse event should be reported separately.

Information reported for the adverse event must include: name of adverse event, date of first onset, peak severity, and relationship to the study drug/device/treatment.

Multiple recurrences of the same adverse event should be reported together.

Note: Any adverse event prompting a change in the administration of study drug/device/treatment must include resolution date, actions taken with respect to administration of study drug/device/treatment, and other treatment for the adverse event.

6-5


Exhibit 6-1-2

REPORTING EXPECTED ADVERSE EVENTS ON CIBMTR RCI BMT STUDIES

SEVERITY GRADE ATTRIBUTION TRANSPLANT CENTER REPORTING REQUIREMENT

5 – Fatal

All attributions Submit study death form to the RCI BMT within 24 hours of death.

Submit death summaries and/or autopsy reports of the expected adverse event to RCI BMT quarterly or as requested.

The summaries should include potential contributing causes of death.

4 – Life-threatening or disabling

All attributions Submit study form(s) capturing data on the expected adverse event to the RCI BMT at the form’s scheduled due date. If the event is not captured on a study from, report using the AE system in an expedited manner.

Note: Selected Grade 3-5 events will be tracked and regularly monitored by the RCI BMT and DSMB as specified in protocol-specific monitoring plans.

3 – Severe

All attributions Submit study form(s) capturing data on the expected adverse event to the RCI BMT at the form’s scheduled due date.

6.5. Adverse Event Reporting and Management Because all or most study participants in CIBMTR RCI BMT trials will be receiving potentially toxic preparative therapy, significant regimen-related toxicity is anticipated. Study CRFs are designed to capture information on these adverse events. Likewise, substantial mortality is anticipated and will be captured via filing of appropriate CRFs. All unexpected adverse events must be reported for the duration of the studies.

6.5.1. FDA IND/IDE Reporting

If a study is under an FDA IND or IDE, all unexpected fatal or life-threatening adverse events are reported to the FDA by telephone or fax within seven calendar days after receipt of the information, following FDA guidelines. All unexpected Grade 3-5 adverse events are reported to the FDA via a written report within fifteen days of receipt of the information (21 CFR 312.32). If the Medical Monitor assesses the event to be unrelated to the study, then the event will not require expedited reporting but will be included in a summary report issued at least twice per year. All expected adverse events (i.e., those listed in the informed consent, product inserts, or study materials) not covered under the above requirements need not be reported via the AE Form. They will be captured on other CRFs. Although death and graft failures are not considered unexpected post-transplant events, they are reported to the FDA via annual reports.

6-6


The RCI BMT is responsible for reporting to the FDA on at least an annual basis. If a study is under an FDA IND or IDE, this timeframe still applies for reporting to the NHLBI.

6.5.2. Monitoring Toxicity

The Protocol Team for each study develops a protocol-specific Toxicity Form. The items on the Toxicity Form are a subset of the CTCAE Version 3.0 relevant to the particular study. The Toxicity Form is submitted at regular time intervals defined by the Protocol Team.

6.6. Guidelines for Reporting Adverse Events to Institutional Review Boards CIBMTR RCI BMT will provide all IRBs associated with the trial 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.

6.6.1. Adverse Event Documentation

AEs definitions and procedures for reporting and monitoring AEs will be documented in the study protocol and/or the MOP. Reporting and monitoring procedures should include the following:

• A notice that a DSMB will be established for this trial;

• The purpose of the DSMB;

• Identification of the DSMB members’ areas of expertise, excluding names;

• The DSMB meeting schedule;

• A description of the DSMB procedures;

• A notice that a Summary Report will be prepared by the CIBMTR RCI BMT within 30 days after each DSMB meeting and will be distributed by the RCI BMT to each Principal Investigator with instructions that each Principal Investigator forward the Summary Report to the local IRBs;

• A description of the Summary Report; and,

• A statement that if safety concerns are identified, the CIBMTR RCI BMT will communicate these promptly to the investigators.

In addition, each CIBMTR RCI BMT study should have a study-specific monitoring plan to ensure adverse events are reported and monitored in a timely manner. The plan will be reviewed

6-7


by the DSMB prior to implementation of the study and executed by the RCI BMT following study initiation. The plan should include a description of procedures for reporting adverse events.

6.6.2. Providing Follow-up Information to Local IRBs

6.6.2.1. Early Phase Multi-Center Clinical Trials

Early Phase trials are not designed to assess clinical benefit. There is less clinical experience with the intervention and usually more concern about possible adverse events. In addition, the outcomes of the trial are not expected to change clinical practice. If the DSMB does not identify any safety, or other protocol concerns, actual listings of percentages of adverse events may be provided to the local IRB. Unless there are safety considerations, this disclosure of adverse event information would be done without separating the data by study group. The CIMBTR RCI BMT will provide a routine summary report of the DSMB meeting within 30 days of the meeting for distribution to participating PIs. It is the responsibility of each PI to forward this information to their local IRB. If the DSMB recommends protocol or informed consent changes, the CIBMTR Chief Scientific Director and the RCI BMT Director will send those changes for distribution to the participating PIs. The communication will include the rationale for such changes and any relevant data. All communication regarding protocol changes will be sent to the RCI BMT within 30 days of the DSMB meeting. Depending on their nature, these changes may need to be implemented rapidly.

6.6.3. Requests from an IRB for Additional Information

If an IRB, whether for a data coordinating center or a clinic, requests information beyond what was agreed to at the beginning of the trial and beyond the above guidelines, the request will be reviewed by the CIBMTR Chief Scientific Director and the RCI BMT Director. Decisions as to how to handle each request will be made jointly, and will depend on the nature of the request, whether or not the DSMB had identified safety concerns, the kind of trial, the stage of the trial, and perhaps whether the IRB is for a coordinating center or a clinic. The CIBMTR RCI BMT will send a letter to the PI stating that the DSMB is carefully monitoring outcomes and adverse events and that if anything occurs that would alter the protocol or informed consent, each investigator and IRB will be informed promptly. The CIBMTR RCI BMT will ask the PI to discuss this letter with their IRB. If this is not acceptable to the IRB, CIBMTR RCI BMT staff will discuss whether or not to provide the data requested by the IRB. If it is decided that data will not be provided and the IRB still objects, participation of the center in the study may cease.

6-8


CCHHAAPPTTEERR 77

HHUUMMAANN SSUUBBJJEECCTTSS PPRROOTTEECCTTIIOONN AANNDD

RREEGGUULLAATTOORRYY PPRROOCCEEDDUURREESS


7. HUMAN SUBJECT PROTECTION AND REGULATORY PROCEDURES

7.1. Institutional Review Board Each transplant center requires internal IRB review prior to participation in a protocol. Documentation of the IRB review must be available at the transplant center and submitted to the CIBMTR RCI BMT office along with a copy of the IRB-approved Informed Consent prior to study initiation. This documentation must be in the form of a photocopy of the IRB approval letter. On an annual basis or as defined by the IRB, the IRB will review the protocol for continuation. The status of annual IRB reviews will be maintained by the transplant center and a copy forwarded to the CIBMTR RCI BMT office. The CIBMTR RCI BMT office will provide a reminder letter to the transplant center within 60 days of IRB expiration to facilitate timely renewal.

7.2. Health Insurance Portability and Accountability Act (HIPAA) It is the responsibility of each participating transplant center to understand their institution’s response and plan to implement the requirements of the Health Insurance Portability and Accountability Act (HIPAA). It is recommended that all participating transplant centers are HIPAA compliant at the time of site activation. The following resources can guide in assuring compliance in addition to the guidance provided by your institution and IRB Chairperson. These websites include: http://aspe.hhs.gov/admnsimp/, http://nchica.org, http://amchipaa.org, and http://irb.mc.duke.edu.

7.3. Office of Human Research Protections (OHRP) Institutional Assurances

Each participating institution must have Federal Wide Assuarance (FWA) from the OHRP and provide the CIBMTR RCI BMT office documentation of this number. Sites identified as not currently have an FWA, are required to obtain a Federal Wide Assurance (FWA) from the Office of Human Research Protections. In order to obtain a FWA, Sites will need to demonstrate understanding of the principles and commitment to 45 CRF 46 and provide information regarding the site’s IRB or Ethics Review Committee. The site IRB must meet the OHRP requirements for membership, standard operating procedures, review of research, voting and additional quorums as identified in the Code of Federal Regulations, 21 CFR 56 and 45 CRF 46.

7.4. Participation of Women, Ethnic Minorities and Children The Code of Federal Regulations state that study participants enrolled in clinical trials must include women, ethnic minorities and children to facilitate potential benefit to all persons at risk for a particular disease, disorder or condition under investigation (45 CRF 46). Inclusion of children (individuals under the age of 21) is encouraged unless there are scientific and/or ethical reasons for exclusion. It is the responsibility of the CTO to review each RCI BMT protocol to ensure that children, women and minorities are included to the fullest extent possible. Sites should make every effort to include these populations in subject recruitment activities.

7.5. Site Regulatory Documents In order for a site to be activated for participation in a CIBMTR RCI BMT clinical trial that is under an IND or IDE, the following materials must be submitted to the CIBMTR RCI BMT Office for entry into a Regulatory Tracking System (RTS):

7-1


FDA 1572 form for IND studies or Investigator Agreement for IDE studies - Statement of site Principal Investigator

Curriculum Vitae – a current CV for the Principal Investigator and Co- Investigator(s)

Letter of IRB approval for each protocol - Sites will be required to submit an initial approval letter from the IRB prior to enrollment of any participation. In addition, sites will also submit annual documentation that a protocol has been reviewed and is approved for continued enrollment and follow up.

IRB Approved Informed Consent Document - must be submitted for each protocol and for an addendum submitted for a protocol along with letter of approval

Federal Wide Assurance number

Financial Disclosure (see Appendix D for sample) For non- IND or IDE clinical trials, an FDA 1572 form is not required to be submitted by the sites to the CIBMTR RCI BMT Office.

7.6. Investigational New Drug or Investigational Device Exemption Application Filing of an IND or IDE application with the FDA is required whenever clinical investigations of an unapproved new drug or biological product or new device are to be studied. In the CIBMTR RCI BMT, a pharmaceutical company providing the product under investigation may determine that the NMDP or a RCI BMT Investigator may serve as the IND or IDE sponsor. It is expected that the RCI BMT Office will provide technical and administrative services to prepare, distribute, and track the IND/IDE application and assume the reporting obligations of the IND/IDE sponsor. In addition, the RCI BMT Office will assume responsibility for coordination and review of annual IND/IDE reports to the FDA and maintain electronic copies of all correspondence.

7-2


CCHHAAPPTTEERR 88

PPUUBBLLIICCAATTIIOONNSS,, PPRREESSEENNTTAATTIIOONNSS,, AABBSSTTRRAACCTTSS,, DDAATTAA RREEQQUUEESSTTSS AANNDD

SSAAMMPPLLEE RREEQQUUEESSTTSS


8. PUBLICATIONS, PRESENTATIONS, ABSTRACTS, DATA REQUESTS AND SAMPLE REQUESTS

8.1. Guidelines The CTO is responsible for developing publication and presentation policies. All policies must be approved by the CTAC before implementation. The Committee reviews all proposed publications and presentations to ensure protection of proprietary information, study participant confidentiality and to determine the public impact of publication and/or presentation of incomplete or premature results. The CTO then will submit a recommendation to the CTAC for final approval. No participating institution, Protocol Team or other individual may present or publish individual findings from work performed on study protocols or work related to RCI BMT meetings and conference calls without approval of the CTO and the CTAC. This includes methodologic or position papers related to CIBMTR RCI BMT protocol development or operations.

8.2. Amendments to Guidelines

Changes to the above policies will be subject to review, amendment and approval by the Steering Committee.

8.3. Continuing Review Regarding Formal Presentation of Data and the Assignment of Writing Teams

Abstracts, presentations, and publications relating to data obtained from RCI BMT protocols or to activities of Protocol Teams are to be submitted to the RCI BMT Office. The RCI BMT Office will have the responsibility for distributing the abstracts and presentations to the CTO for approval. The Chief Scientific Director and the RCI BMT Director will have five business days to make recommendations to the CTAC concerning abstracts and presentations. The RCI BMT Office will have responsibility for distributing the publication documents to the CTO for approval. The CTO will have ten business days to make recommendations to the CTAC concerning publications. If members have concerns about the submitted materials, a conference call will be scheduled to discuss issues raised by the members. After review, the CTO will recommend suitability of the publication to the CTAC for final approval.

8.4. Policy Regarding Oral Presentation of RCI BMT Related Data A notable exception to the above policy relates to oral presentation to local groups limited to the design or rationale of the RCI BMT sponsored protocol. Individuals making such presentations must assure that the material will not be recorded, published or represented in any way without approval of the CTO.

8.5. General Policy Research activities of the RCI BMT are intended to contribute generalizable knowledge to the field of hematopoietic cell transplantation (HCT). Definitive contributions are made through publications in the peer-reviewed literature. Abstracts, public presentations, electronic postings and sharing of data also contribute importantly to public knowledge, but do not substitute for peer-reviewed publications and are, therefore, of lower priority.

8-1


8.5.1. Approvals and Submission

The RCI BMT is responsible for submission of the final manuscript and for obtaining written approvals from all authors. Each author, the RCI BMT Office shall receive a final copy of the submitted manuscript. Review, correction and return of galley proofs are the joint responsibility of the lead author and the Protocol Statistician.

8.5.2. Manuscript Requirements

All manuscripts of the CIBMTR RCI BMT are subject to the following requirements:

8.5.2.1. Titles

Whenever possible the manuscript title must include the words “Center for International Blood and Marrow Transplant Research”

8.5.2.2. Acknowledgments

Each manuscript must acknowledge all funding sources for the study including sources of funding and aid, e.g. drugs, reagents, etc, from other groups, herein defined as Contributors providing support (see below).

8.6. Manuscripts Describing Data from CIBMTR RCI BMT Trials A primary manuscript reporting the results of each CIBMTR RCI BMT trial is prepared and submitted in a timely manner upon completion of the study. No clinical trial results are released, presented or published prior to conclusion of the study and release of the final dataset by the Protocol Team.

8.6.1. Data Analysis

The statistical analysis of trial data is performed by the CIBMTR. Final decisions about patient outcomes and endpoints are the responsibility of the Protocol Chair, Protocol Officer and Protocol Statistician. Upon completion of the statistical analysis the RCI BMT Office issues the Technical Report of the study. In general, the Technical Report is available within two months of locking the trial dataset. The Protocol Chair will monitor progress toward completion of the Technical Report. The Protocol Chair may ask the RCI BMT Director to assist with addressing delays in the completion of the Technical Report.

8.6.2. Writing Responsibilities

Completion of the primary study manuscript is the responsibility of the Protocol Chair. The first draft manuscript is completed within two months of receiving the Technical Report and necessary supplemental analyses. Co-authors shall have access to the study Technical Report and shall be afforded ample opportunities to contribute to completion of the manuscript. If the Protocol Chair is unable to complete the first-draft manuscript in a timely fashion, the CTO has the responsibility to address the delay. If necessary, the CTO may assign first-draft responsibility to another author who will become the lead author on the manuscript.

8-2


Upon completion, the first-draft manuscript is submitted to the RCI BMT Office for distribution to all authors. Author inputs are used to generate subsequent drafts and the final manuscript. Disagreements between authors are settled by discussion and consensus whenever possible or, if consensus cannot be achieved, by majority vote of the authorship. If necessary, disagreements are brought (by any reasonable communication mechanism) before the CTAC for discussion and decision by simple majority rule. In general, the time from completion of the first-draft manuscript and the final manuscript submission does not exceed four months.

8.6.3. Acknowledgement of Donations and Other Protocol Support

8.6.3.1. Donations

The Contributors must agree to provide support as a donation. The Contributor understands that the donation does not provide the Contributor with any rights to the data, publications, intellectual property, revenue, or any other assets that may be generated by the Project unless specifically identified in a Memorandum of Agreement.

8.6.3.2. Data and Publications

The CIBMTR RCI BMT agrees that it will provide the Contributor, when requested, with a draft copy of all publications and a summary of data resulting from the Project when such information is ready to be made available to the public. The Contributor will have up to 30 consecutive days to review information, submit questions and provide comments with the express understanding that all decisions regarding publication will be at the sole discretion of the investigators. An exception to the above is if the Contributor’s objections relate to information provided by the Contributor as confidential prior to commencing the research Project.

8.6.4. Attributions

Each primary study manuscript must include a listing of all participating centers and the responsible study physician at that center.

8.6.5. Timelines

Locking of the dataset – 2 months. Unforeseen delays in the dataset verification will be communicated to the Protocol Chair by the RCI BMT Office.

Dataset closure to Technical Report – 2 months.

Technical Report to first draft manuscript – 2 months.

First draft manuscript to submission – 4 months.

8.7. Authorship

The primary requirement for authorship of a CIBMTR RCI BMT publication is a substantive contribution to the research effort. This may include activities in the following areas: hypothesis generation, concept development, protocol development, study implementation, subject enrollment, data collection, data analysis, and manuscript preparation and finalization. In most instances, contributions in several areas must occur, and in every instance, authors are expected to contribute to manuscript preparation and finalization.

8-3


8.7.1. Authorship Eligibility Requirements

Each member of the Protocol Team has eligibility for authorship on the final primary manuscript from the study. In addition, each center Principal Investigator whose center enrolls at least one subject in the study is eligible for authorship. Additional authors may be invited at the discretion of the Protocol Chair with approval of the CTO. Eligibility for authorship does not guarantee authorship. Eligible authors must still make substantive contributions.

8.7.2. Establishing the Order of Authors

The person with primary responsibility for writing the manuscript, normally the Protocol Chair, will be the first author. The lead protocol statistician will be the second author. The senior (last) author on the manuscript will be selected by the Protocol Chair, subject to review by the Protocol Team. All additional authors will be listed according to accrual.

8.7.3. Removing Authors

An eligible author may be removed from the final manuscript upon failure to make substantive contributions to the overall project. The lead author may request that another author withdraw from authorship. The CTO shall adjudicate authorship disputes be simple majority rule.

8.7.4. Authorship on Joint Studies

For some studies, the CIBMTR RCI BMT will partner with other organizations. In these instances, every effort should be made to decide authorship issues prior to study initiation. Particularly, lead authors and senior authors should be determined in advance.

8.8. Abstracts, Public Presentations, Electronic Postings 8.8.1. General

Abstracts, public presentations of study data and electronic postings of study data must follow the same processes outlined for primary publications, but do not require the same levels of scrutiny and are handled expeditiously. Abstracts, presentations or electronic postings cannot be prepared before completion of the final study Technical Report. The CIBMTR Chief Scientific Director and the RCI BMT Director or the CTO may approve requests for abstract submission, public data presentation or electronic data posting. The RCI BMT Office shall have the right to review and prioritize approvals based upon the availability of required resources.

8.8.2. Abstracts

Authorship for abstracts will generally be restricted to the Protocol Team. When necessary, the Protocol Chair may invite up to two additional authors who are not members of the Protocol Team. All abstract authors must have made substantive contributions to the study. Proposals for abstract submissions must be initiated well in advance of the abstract submission deadline. Abstracts are lower priority than peer-reviewed publications, but receive higher priority than public presentations and electronic postings.

8-4


8.8.3. Public Presentations and Electronic Postings of Study Data

In general, a complete set of summary slides is prepared by the RCI BMT Office upon the completion and analysis of each CIBMTR RCI BMT study. Study results will also be posted to the CIBMTR RCI BMT website. Individual investigators who wish to prepare additional slides for public presentation must utilize data from the final Technical Report. Such presentations must also be submitted to the RCI BMT Office for submission to the The CIBMTR Chief Scientific Director and the RCI BMT Director or the CTO for review and approval. Each such presentation must also acknowledge the authors, the funding agencies and the participating centers. Electronic posting of study data must not occur prior to publication in a peer-reviewed journal. Any individual or organization requesting data for electronic posting may be required to demonstrate that copyrights will not be infringed. In the absence of such evidence, the request may be refused.

8.9. Ancillary Studies, Laboratory Studies, Position Papers and Technical Reports 8.9.1. General

Ancillary studies, laboratory studies, position papers and technical reports are to be submitted to the RCI BMT Office and must follow the same processes outlined for primary publications, but do not require the same levels of scrutiny. The CIBMTR Chief Scientific Director and the RCI BMT Director or the CTO should approve requests for ancillary studies, laboratory studies, position papers and technical reports. The RCI BMT Office shall have the right to review and prioritize approvals based upon the availability of required resources.

8.10. Data Requests

CIBMTR RCI BMT data are available to investigators, network centers and the general public. Access is governed by the policies and procedures presented in this chapter. All data requests must follow these policies and procedures.

8.10.1. Types of Data Available

Data available through CIBMTR RCI BMT are generally those collected in the course of preparing, implementing and conducting clinical trials.

8.10.2. Stipulations for Data Requests

1. A request for data should be made using the form or forms(s) specified by CIBMTR RCI BMT.

1. If approved, data can be sent by mail, fax or e-mail. 2. If a request is not approved, the requestor is contacted and informed of the decision. 4. Data may have restrictions on their use (see below). 5. Unless otherwise specified, any publication, electronic posting or presentation of RCI

BMT data must receive RCI BMT review and approval prior to release. 6. Investigators must acknowledge RCI BMT support in the manuscript and submit a copy

of the final printed manuscript to the RCI BMT.

8-5


8.10.3. Requesting Data

8.10.3.1. Access to Data and Classification of Data

Anyone may submit a data request. Data are provided free of charge to individuals and nonprofit organizations. For-profit organizations may be asked to reimburse the RCI BMT’s costs for services.

8.10.3.2. Types of Data Requests

8.10.3.2.1. Aggregated data request

Aggregated data requests are made by a physician, a transplant center or CIBMTR staff on behalf of a patient. These data can only be used for patient counseling, and cannot be published, presented or electronically posted without the prior written permission of the RCI BMT. These requests receive high priority.

8.10.3.2.2. Request for patient-specific data

Patient-specific data are not made available unless the request is made by an agency or individual with legal authority or is accompanied by an appropriate, signed information release executed by the patient, the patient’s legal guardian or the patient’s heirs.

8.10.3.2.3. Permission-to-publish data request

Permission-to-publish data requests are made by individuals for the purpose of preparing review articles or similar presentations, including requests to reproduce previously published figures or graphs. These requests are generally of limited scope and would not ordinarily involve iterative requests for additional data or modifications to the analysis. In all cases where material is publicly presented, published or posted, proper acknowledgement to the CIBMTR RCI BMT is required. Additionally, acknowledgements of the CIBMTR RCI BMT funding sources, including supply of drugs, reagents, etc. from other groups (Contributors), CIBMTR RCI BMT staff or others who have assisted may be required for certain data. The CIBMTR RCI BMT will provide the proper attribution at the time the material is reviewed. It is the requestor's responsibility to ensure that this information is included.

8.10.3.2.4. Center-specific data request

In general, center-specific data are available only to the center itself. Center-specific requests are made by the staff at CIBMTR centers for internal use only. These requests receive high priority.

8.11. Sample Requests The first priority for releasing CIBMTR RCI BMT samples and specimens is research that may contribute new information to the study for which the samples were collected. Requests that propose to use samples or specimens in research unrelated to the interests of CIBMTR RCI BMT receive second level priority. All sample or specimen requests must follow these policies and procedures.

8-6


8.11.1. Types of Samples Available

The types of samples available will depend upon the particular protocol for which they were collected. Samples may include viable cells, blood, serum, plasma, extracted DNA, blood spots, etc. Specimens may include body fluids or tissues biopsies. It is anticipated that whatever the type of sample or specimen, on occasion, unused materials will remain after the completion of the trial for which they were collected.

8.11.2. Overview of the Request Process

1. A request for data or samples should be made using the form or forms(s) specified by CIBMTR RCI BMT.

2. If approved, samples are shipped directly to the investigator(s). 3. If a request is not approved, the requestor is contacted and informed of the decision. 4. Samples may have restrictions on their use (see below). 5. Unless otherwise specified, any publication, electronic posting or presentation of

CIBMTR RCI BMT data derived from CIBMTR RCI BMT samples must receive CIBMTR RCI BMT review and approval prior to release.

6. Investigators must acknowledge CIBMTR RCI BMT support in the manuscript and submit a copy of the final printed manuscript to the CIBMTR RCI BMT.

8.11.3. Requesting Samples

8.11.3.1. Access to Samples

Representatives of CIBMTR participating centers and investigators or research groups may request access to research samples collected by the CIBMTR.

8.11.3.2. Restrictions

The intended use for these samples is to facilitate research projects. 1. Research projects may require approval of the investigator’s local IRB and must be

allowable under the Informed Consent Document. 2. Commercial use of samples from the CIBMTR RCI BMT is strictly forbidden without

the prior written consent of the CIBMTR RCI BMT. 3. Third-party distribution of any of the samples from the CIBMTR RCI BMT is strictly

forbidden without the prior written consent of the CIBMTR RCI BMT. 4. Upon request, any unused samples shall be returned to the CIBMTR RCI BMT. 5. After testing is complete, samples must be disposed of according to local and state

biohazardous waste laws. Samples must not be retained indefinitely. 6. Use of research samples may be restricted by the nature of the consent obtained at the

time of collection. In the absence of consent for the intended use, the CIBMTR RCI BMT may, at its discretion, facilitate obtaining additional consents, which may require charges to the requestor. Samples provided by persons who subsequently died are considered property of the CIBMTR RCI BMT, but may still be subject to restrictions on their use as determined by CIBMTR RCI BMT.

8-7


8.11.3.3. Disclaimer

There are no warranties, express or implied, including, without limitations, any implied warranty of merchantability or fitness for a particular purpose. Those who receive samples from the CIBMTR RCI BMT are responsible for safe storage, handling and use of these samples. The CIBMTR RCI BMT is not liable for any damages or injuries resulting from receipt and/or improper, inappropriate, unintended, wrongful or negligent handling or use of a sample. While every effort is made to ensure authenticity, purity or typicality of the samples, the CIBMTR RCI BMT is not liable for any damages or injuries arising from misidentification, misrepresentation, lack of purity or atypicality of the samples.

8.11.3.4. Acknowledgements

In all cases where data derived from CIBMTR RCI BMT research samples is publicly presented, published or posted, proper acknowledgement of CIBMTR RCI BMT is required. Additionally, acknowledgements of the CIBMTR RCI BMT funding sources, including supply of drugs, reagents, etc. from other groups (Contributors), CIBMTR RCI BMT staff or others who have assisted may be required for certain situations. The CIBMTR RCI BMT will provide the proper acknowledgement at the time the material is reviewed. It is the authors’ responsibility to ensure that this information is included.

8.11.4. How Requests Are Reviewed/Approved for Samples and Corresponding Data

Requests for samples and corresponding data are reviewed by Protocol Chair of the protocol for which the samples were collected. The Chair will determine if further review by the entire Protocol Team is required. Review of a data or sample request is generally complete within 20 business days. Decisions of the Protocol Team Chair may be appealed to the CTO. Appeals must be filed with the RCI BMT Office within 20 working days of a decision.

8.11.5. How Samples Are Distributed to Requestor

Samples are shipped as specified by the requestor. The requestor may be required to pay additional shipping charges.

8.12. Definitions 8.12.1. Journal Articles

A journal article is any document submitted to a professional journal listed in the Index Medicus. All material prepared for submission to a professional journal must be submitted to the RCI BMT Office for review and approval.

8.12.2. Presentations

A presentation is any oral communication in a local, regional, national or international forum other than an internal presentation given at the presenter's own center.

8-8


8.12.3. Electronic Media

Electronic media includes publication or posting to a website, electronic journal, or any other medium using the Internet.

8-9



8-10


CCHHAAPPTTEERR 99

SSHHIIPPPPIINNGG IINNSSTTRRUUCCTTIIOONNSS


9. CIBMTR RCI BMT SHIPPING INSTRUCTIONS USING FEDERAL EXPRESS Shipping of samples to the NMDP repository and/or laboratories will be at the expense of the National Marrow Donor Program® (NMDP), on behalf of the CIBMTR RCI BMT. The NMDP has negotiated rates with Federal Express specific to the CIBMTR RCI BMT. RCI BMT will provide protocol specific packaging and shipping instructions to sites at time of initiation. Specimen packaging will follow current IATA guidelines. Pre-printed airbills and lab requisitions will be provided to sites.


APPENDIX A Clinical Trials Advisory Committee Charter


CENTER FOR INTERNATIONAL BLOOD AND MARROW TRANSPLANT RESEARCH®,

RESOURCE FOR CLINICAL INVESTIGATION IN BLOOD AND MARROW TRANSPLANTATION (CIBMTR RCI BMT)

CLINICAL TRIALS ADVISORY COMMITTEE CHARTER FEBRUARY 2007

DESCRIPTION/OBJECTIVE The Center for Blood and Marrow Transplant Research, Resource for Clinical Investigation in Blood and Marrow Transplantation (CIBMTR RCI BMT) Clinical Trials Advisory Committee (“The CTAC”) will serve as an independent advisory body for CIBMTR RCI BMT proposals. The primary function of the CTAC is to review and provide recommendations regarding proposals submitted to the CIBMTR RCI BMT relative to scientific merit, feasibility, and alignment with the CIBMTR’s scientific agenda. On occasion the CTAC may be asked to provide input for protocols in development or active protocols within the RCI BMT. The CTAC will have an interdisciplinary membership with expertise in hematopoietic stem cell transplantation and the conduct of clinical trials. The Committee will be supported by the RCI BMT Clinical Trials Office (CTO). RCI BMT MISSION STATEMENT 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 RCI BMT will provide statistical expertise and data management services for multi-center phase I/II trials. While not a funding agency, the CIBMTR, through the RCI BMT, will partner with investigators to seek necessary support for trial completion. The goal of the RCI BMT is to bridge the gap between single-center studies and the larger phase II and III studies conducted by the Blood and Marrow Transplant Clinical Trials Network (BMT CTN), also coordinated by the CIBMTR in collaboration with the National Marrow Donor Program and the EMMES Corporation. In general, RCI BMT studies should meet the following criteria:

• Interventional trials requiring 10 or fewer centers and 50 or fewer patients • Non-interventional studies that require direct interaction with study subjects (e.g.

interview studies of long-term survivors; would not include studies that require only chart or database review)

• Have some pilot data available or a plan with which to obtain those data prior to initiating the trial

The focus of the RCI BMT will be to facilitate studies addressing transplant-related issues. For example:

• Evaluation of new conditioning regimens • Evaluation of different stem cell sources • Interventions to assess or improve quality of life


• Novel interventions to prevent or treat post-transplant complications including relapse of the primary disease

RESPONSIBILITIES

• Key responsibilities of the CTAC are to: o Assess submitted proposals for scientific merit, feasibility, and alignment with

scientific agenda; o Advise the RCI BMT Executive Committee on priority of proposed studies; o Review progress of ongoing studies.

MEMBERSHIP

• CTAC Composition o Minimum of ten volunteer members

Nominated by the CIBMTR Nominating Committee Appointed by the CIBMTR Executive Committee Three year terms; renewable one time Composed of adult & pediatric transplant physicians including persons

versed in representing donor interest (i.e.: transfusion medicine physician) and non-physicians with experience in patient and donor issues

o Individuals with specific expertise may be invited by the CTAC chair to serve as consulting (ad hoc) members for review of a specific study

All appointed and consulting (ad hoc) members will have equal voting rights pertaining to the particular study(s)

o Ex officio members from the RCI BMT Executive Committee: RCI BMT Director, Executive Secretary, PhD Statistician, Chief Medical Officer of the NDMP, CIBMTR Research Advisor, CIBMTR Chief Scientific Director, and one additional scientific director

• Roles within CTAC

o Chairperson Appointed by CIBMTR Chairperson from CIBMTR volunteer members

appointed by Executive Committee to a two-year renewable term Develops meeting agendas in conjunction with RCI BMT Director and

CTO staff Responsible for management of meetings in conjunction with the RCI

BMT Director o Vice Chairperson

Appointed by CIBMTR Chairperson from CIBMTR volunteer members appoints by Executive Committee to a two-year non-renewable term

Serves as Chairperson if Chairperson unavailable o RCI BMT Director

CIBMTR staff member Oversight of RCI BMT daily operations Assists the Chairperson with meeting agendas, organization, and

management


Participates in the open session of RCI BMT Monitoring Board Meetings Updates the CTAC on all current studies Responsible for formal notification of study/proposal status to

investigators o Executive Secretary

Representative from RCI BMT CTO Provides logistical management and support to CTAC including drafting

of meeting minutes and interim data summary reports Primary contact for all CTAC interactions Facilitates timely communication of CTAC

actions/recommendations/feedback to CTO

• CTAC Conflict of Interest Policy o All financial, scientific and/or other conflict of interests relative to proposals or

studies under consideration must be declared per established CIBMTR guidelines o Signed “Conflict of Interest” statement required from all members

MEETINGS

• The CTAC will meet at least three times yearly and as frequently as quarterly o Scheduling frequency contingent upon:

Number of active protocols Total number of proposals requiring review

o May occur either in-person or via conference call o Requires a quorum of at least 5 volunteer members

• At least one week prior to each meeting, the Executive Secretary will distribute the

following materials electronically to all CTAC members: o Information regarding Open Trials

Number of sites activated Accrual to date

o Information Packets for Proposals Proposal Summary of CIBMTR Working Committee Chair reviews, without

identifier Accrual estimates, based on CIBMTR database Other information as requested by CTAC Chair

• CTAC Meeting Minutes

o Will be drafted by the Executive Secretary and reviewed by the CTAC Director o Will list all CTAC conclusions and recommendations o Will be distributed to membership within two weeks following a meeting


APPENDIX B Data Safety Monitoring Board Charter

CENTER FOR INTERNATIONAL BLOOD AND MARROW TRANSPLANT RESEARCH,

RESOURCE FOR CLINICAL INVESTIGATION IN BLOOD AND MARROW TRANSPLANTATION (CIBMTR RCI BMT)

MONITORING BOARD CHARTER JULY 2006

DESCRIPTION/OBJECTIVE The Center for Blood and Marrow Transplant Research ™, Resource for Clinical Investigation in Blood and Marrow Transplantation (CIBMTR RCI BMT) Monitoring Board (“The Monitoring Board”) will serve as an independent advisory body for all CIBMTR RCI BMT studies. The primary function of the Monitoring Board will be to perform ongoing assessment and monitoring of CIBMTR RCI BMT studies relative to scientific merit/validity, safety and efficacy. The Monitoring Board will be comprised of an interdisciplinary membership with expertise in hematopoietic stem cell transplantation and the conduct of clinical trials. Oversight will fall under the auspice of Research Administration at the National Marrow Donor Program® (NMDP). RESPONSIBILITIES

• Key responsibilities of the Monitoring Board

o To offer advice concerning the continued scientific merit and/or validity of each ongoing study.

o To provide continual assessment and monitoring of study participant safety; particularly with respect to the magnitude and impact of any adverse or severe adverse events.

o To provide ongoing assessment and monitoring of all study specific prescribed treatment protocols.

o To review and assess study specific site performance data such as study recruitment and accrual, protocol adherence and data quality.

o To recommend the continuation, amendment or termination of each ongoing study based upon regularly scheduled review of interim data results.

o To ensure study subject confidentiality as well as that of all study data and the conclusions reached as a result of the monitoring process.

• Additional individual Monitoring Board member responsibilities

o To thoroughly review and understand all study protocols and (if

applicable) Investigator’s brochures o To keep current of pertinent information (i.e.: newly published results)

external to CIBMTR RCI BMT studies which may impact the safety, efficacy or scientific validity of such studies

MEMBERSHIP

• Monitoring Board Composition

o Minimum of seven members o Invited and appointed by The Center for Blood and Marrow Transplant

Research ™ (CIBMTR) o Two or three year terms; renewable one time o Ideally, blend of adult vs. pediatric transplant physicians and at least one

physician versed in representing donor interests (i.e.: transfusion medicine physician)

o Minimum of one statistician o Individuals with specific expertise may be requested to serve as consulting

(ad hoc) members at any time in order to adequately meet monitoring needs of each individual study

o All appointed and consulting (ad hoc) members will have equal voting rights pertaining to the particular study(s) being monitored

• Specific Roles within Monitoring Board

o Chairperson

Appointed by CIBMTR Clinical trials experience required Prior Scientific Review Committee (SRC) and/or Data Safety

Monitoring Board (DSMB) experience desired Primary contact for all Monitoring Board interactions Develops meeting agendas in conjunction with CIBMTR Assumes overall responsibility for oversight/management of

meetings Facilitates timely communication of Monitoring Board

actions/recommendations/feedback to CIBMTR o Vice Chairperson

Appointed by Chairperson and CIBMTR Serves as Chairperson if Chairperson unavailable

o Executive Secretary Representative from NMDP Research Administration Provides logistical management and support to Monitoring Board

including drafting of meeting minutes and interim data summary reports

• Monitoring Board Membership Criteria

o All financial, scientific and/or other conflict of interests relative to studies

being monitored must be declared per established CIBMTR guidelines o Signed “Conflict of Interest” statement required by all members o Signed NMDP contract or agreement

MEETINGS

• Monitoring Board Start-Up Meeting

o Prior to enrollment of any subjects in studies to be monitored o Preferably held in-person o Main focus to address administrative, operational details including:

Development of procedures for review of study protocols and informed consent documents; approval of study initiations etc.

Determination of data type and format required for interim reviews Scheduling of future meetings Definition of membership quorum Establishment of method and timelines for distribution of review

materials to membership prior to subsequent meetings Appointing of Chairperson and Vice-Chairperson Signing of Conflict of Interest statements by appointed members Review and approval of Monitoring Board Charter

• Regularly Scheduled Meetings

o To occur at least annually and as frequently as quarterly o Scheduling frequency contingent upon:

Total number of studies requiring monitoring Total amount of accumulated study data Degree of inherent risk associated with each involved study

o May occur either in-person or via conference call o Two distinct sessions:

Open Session • New study discussions:

o Principal Investigator (PI) presentation and questions

o Review of study protocols o Review of informed consent documents o Approval of study initiation

• Ongoing study general information discussions: o Patient accrual o Protocol compliance o Logistical problems encountered to date o Presentation or discussion of either patient or

treatment specific data may not be addressed • Attendance by:

o Voting members of Monitoring Board o PI and his/her staff o CIBMTR staff o Appropriate study statisticians

Closed Session • Quorum must be present • Discussions concerning:

o Any and all safety data o Study results o Outcome data (if appropriate) o Information to result in formulation of study-

specific recommendations o Efficacy data (only if requested and approved in

advance; study stopping criteria must be clearly defined and operational)

o Actions to amend or terminate a study • Attendance by:

o Voting members of Monitoring Board o Executive Secretary o All other attendees (study statisticians, CIBMTR

staff) by Monitoring Board invite only

• Emergency Meetings

o May be called at any time by either Monitoring Board Chairperson, Vice-Chairperson or appropriate CIBMTR representative

o Used to address any emergent safety or efficacy issues regarding studies being monitored

o May be held in-person or via conference call o To follow same format as regularly scheduled meetings

DOCUMENTATION/REPORTS

• Study-Specific Interim Reports

o Generated prior to each Monitoring Board meeting o Prepared by appropriate study statistician and/or other CIBMTR staff o Distributed to Monitoring Board membership:

Electronically, via US mail and/or via overnight courier service Scheduled for receipt well in advance of scheduled meeting

o Exact content/format to be determined at initial Monitoring Board meeting; will be dependent upon specific study and data being collected.

• Monitoring Board Meeting Minutes

o Responsibility of Executive Secretary to draft o To include all Monitoring Board conclusions and recommendations o Distribution to entire membership within two weeks following a meeting

• Interim Data Summary Reports

o Responsibility of Executive Secretary to draft o Study-specific o Must conclude with formal recommendation (achieved by majority

Monitoring Board vote) to continue, amend or terminate study o Distributed to Monitoring Board membership within two weeks following

meeting o Approval by Monitoring Board Chairperson and full Monitoring Board

membership required o Distribution to appropriate CIBMTR representative o Forwarded to appropriate study PI by CIBMTR o Distribution of report content to co-PIs and/or applicable Institutional

Review Boards (IRBs) by study PI o CIBMTR to notify PI of study termination

SECURITY/CONFIDENTIALITY

• Monitoring Board members will not be blinded to study treatment protocols thus security and confidentiality must be assured

• Each member must agree to complete confidentiality with respect to: o All Monitoring Board discussions and recommendations o All distributed materials including meeting minutes and summary reports

• Implementation of additional security measures to include: o Limiting access to interim study data to Monitoring Board members only o Destruction of “closed” session reports at conclusion of meetings o Archiving meeting minutes and summary reports within secure files of

NMDP Research Administration COMPENSATION

• Individual member reimbursement to include: o Travel expenses incurred for meeting participation o $200 per meeting for participation

APPENDIX C Study Proposal Application and Template

Prospective Study Proposal Application

Date: Study Chairperson Name: Institution: Mailing Address: Phone Number: Email Address: Pager Number: Fax Number: Best Way to Contact: Email Phone Fax Pager Other Proposed Center(s): (if applicable) Type of Service: Prospective Data Collection/Follow Up (Select all that apply) Prospective Intervention Health Services Ancillary Lab Other: Potential Funding Source: Funding: Secured Source: Institutional Unknown Industry

Anticipated Other: Grants (specify)

Protocol Title: Protocol Title: Background and Study Rationale Background and Study Rationale Primary Hypothesis Primary Hypothesis Patient Population Patient Population Inclusion Criteria Inclusion Criteria Exclusion Criteria Exclusion Criteria Treatment Plan Treatment Plan Primary Objectives Primary Objectives Secondary Objectives Secondary Objectives Study Design Study Design

Phase I Phase II Phase III Other:

Blinded Randomized Other:

Accrual Estimate

Accrual Period

Follow-Up Period

References

CIBMTR USE ONLY

Date Received: Initials: Tracking ID#: Review Date:

Center for International Blood and Marrow Transplant Research (CIBMTR) 3001 Broadway St. NE Suite 110 Minneapolis, MN 55413-1753 www.cibmtr.orgPhone: 612-884-8600 Fax: 612-884-8661 Email: [email protected]

http://www.cibmtr.org/

mailto:[email protected]

APPENDIX D

FINANCIAL DISCLOSURE EXAMPLE

FINANCIAL DISCLOSURE STATEMENT

RCI BMT Protocol 07-REV: "Evaluation of lenalidomide as maintenance therapy post allogenic hematopoietic cell transplantation for high-risk multiple myeloma"

I, as a participating clinical investigator in protocol [xxx], am submitting the following information in accordance with 21 CFR Part 54.

I, (including my spouse and dependent children) DO / DO NOT (circle the appropriate answer) have any financial arrangement or interest that are required to be disclosed as follows:

Any financial arrangements with Celgene (manufacturer of Revlamid) where compensation would be enhanced based on the outcome of the study. [21 CFR 54.2(a)]

Any ownership interest, stock options, or other financial interest in the parties named above whose value exceeds $50,000 during the time I am involved with the study and for one full year after completion of the study. [21 CFR 54.2 (b)]

Any intellectual property rights (e.g. patents, copyrights, and royalties from such rights) resulting from participation in the study. [21 CFR 54.2 (c)]

Any fees for consulting, honoraria provided or promises of a grant to fund ongoing research by the sponsor that exceed $25,000 exclusive of the cost of conducting the study, during involvement with the study and for one full year after completion of the study. [21 CFR 54.2 (f)]

If any of the above items are checked it will indicate that you DO have disclosable information. Please describe details of this information in the space below: In accordance with 21 CFR 54, I declare that the information provided on this form is, to the best of my knowledge and belief, true, correct and complete. Furthermore, if my financial interests and arrangements, or those of my spouse and dependent children, change from the information provided above during the course of this study or within one year after the last patient has completed the study as specified in the protocol, I will notify the BMT CTN and NHLBI promptly. Signature of Investigator ___________________________________________ Date ____________

Name of Investigator (printed) _______________________________________________________ Institution (printed) ________________________________________________________________