Clinical Research Operations Manual


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West Virginia Clinical and Translational Science Institute
CLINICAL RESEARCH OPERATIONS MANUAL
“The Gold Book”
Director for Clinical Research
TBN
Biostatistics Core Facility
Dr. Matthew Gurka
Clinical Trials Research Unit
John O. Naim, Ph.D. Director Susan L. Collins, MSN, RN, CCRC, Program Manager
Leah Darr, BS, CCRP, Regulatory Manager
Clinical Trials Working Group
Dr. John O. Naim, Chair TBN, Co-Chair
Laila Wallace, CTWG Coordinator
Second Edition, June 19, 2014©

Table of Contents
Introduction and Background ...................................................................................................................... i The Gold Book............................................................................................................................................. ii Abbreviations ..............................................................................................................................................iii
I. Clinical Trials Working Group (CTWG)............................................................................................. 1 II. Protocol Review and Monitoring .................................................................................................... 2
A. Protocol Concepts/LOIs Review .................................................................................................. 3 B. Review of New Protocols ............................................................................................................ 3 C. Guidelines for Initiation of an Amendment ................................................................................ 4 III. Investigator Initiated Protocol Development .............................................................................. 4 A. Protocol Development Guidelines .............................................................................................. 4 B. Available WVCTSI Resources to Assist In Protocol Development................................................ 5 C. Investigator Responsibilities ....................................................................................................... 8 D. Human Subject Protection and GCP Training............................................................................ 10 E. Informed Consent ..................................................................................................................... 11 F. Data Safety and Monitoring Plan .............................................................................................. 12 G. Serious Adverse Event Reporting.............................................................................................. 15 H. Data Acquisition........................................................................................................................ 16 I. Eligibility Verification ................................................................................................................ 16 J. Budget Development ................................................................................................................ 18 K. Trial Registration....................................................................................................................... 18 L. Protocol Review and Activation ................................................................................................ 19 M. Funding Guidance ..................................................................................................................... 23 N. Collaborating Institutions ......................................................................................................... 24 IV. Industry Sponsored Protocols ................................................................................................... 26 A. Confidentiality Disclosure Agreement ...................................................................................... 26 B. Feasibility Assessment .............................................................................................................. 26 C. Budget Review and Cost Analysis ............................................................................................. 27 V. Core Descriptions and Processes .................................................................................................. 27 A. Bioinformatics and Biostatistics Core Facility ........................................................................... 27 B. Biospecimen Processing Core ................................................................................................... 27 C. Clinical Trials Research Unit ...................................................................................................... 28 D. Clinical Pharmacology Shared Resource Core Facility............................................................... 28 E. Genomics Core Facility.............................................................................................................. 28
Second Edition, June 19, 2014©

F. Molecular Medicine Core Facility ............................................................................................. 29 G. Pathology and Histology Services ............................................................................................. 29 H. Electron Microscopy Core Facility............................................................................................. 30 I. Center for Advanced Imaging ................................................................................................... 30 J. Flow Cytometry Core Facility .................................................................................................... 31 K. Tissue Bank and Research Laboratory ...................................................................................... 31 Appendices ........................................................................................................................................... 33 Appendix 1 – Clinical Trials Working Group Members ..................................................................... 34 Appendix 2 - Protocol Templates ..................................................................................................... 35 Appendix 3 – Investigator Responsibilities ....................................................................................... 37 Appendix 4 – Data and Safety Monitoring Plan................................................................................ 38 Appendix 5 – Sample Budget and Worksheet .................................................................................. 44 Appendix 6 – Billing Order Set.......................................................................................................... 47 Appendix 7 – Study Coordinator Assessment Tool........................................................................... 48 Appendix 8 – CTRU Application ........................................................................................................ 50 Appendix 9 – CTWG Reviewer Form................................................................................................. 52 Appendix 10 – CTWG Pharmacy Review Form ................................................................................. 54 Appendix 11 – CTWG BioStat Review Form...................................................................................... 55 Appendix 12 – WVCTSI Research Services Directory ........................................................................ 56
Second Edition, June 19, 2014©

Introduction and Background
The policies and procedures in the second edition of the West Virginia Clinical and Translational Science Institute’s Clinical Trials Operations Manual (hereafter referred to as the Gold Book) were adapted from the Mary Babb Randolph Cancer Center Clinical Trials Operations Manual (referred to as the Blue Book). The West Virginia Clinical and Translational Science Institute wishes to both acknowledge and thank the Mary Babb Randolph Cancer Center Clinical Trials Research Unit for their support and guidance as we continue to build our clinical research enterprise.
There are elements in the second edition of the Clinical Trials Operations Manual that are in the formative phases of development as our research mission and programs continue to evolve. However, those policies and procedures that are not yet mature or implemented are designated To Be Established or To Be Developed and connoted by the abbreviation of TBE and TBD respectively, in areas of the operations manual text herein. Additionally, several Clinical Trials Research Unit (CTRU) and scientific administrative positions are To Be Named, which are connoted by TBN. Subsequent editions of the Gold Book will capture these new requirements as they come online.

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The Gold Book
The Gold Book provides a roadmap for the conduct of Good Clinical Practice (GCP) based clinical studies. It has been developed to provide transparency to the process of developing, executing and monitoring clinical and translational research projects uniformly throughout the State. Further it should help to facilitate the integration of research operations across WVCTSI participating institutions by standardizing policies and procedures for the conduct of clinical trials and population studies.
The clinical research operation manual (Gold Book) applies to all WVCTSI related clinical research not involving cancer patients. This manual applies to faculty participating in clinical research for all participating institutions conducted under the auspices within WVCTSI.

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AE CAP CDA CITI CLIA COI CRFs CTRU CTWG CV DMC DSMB DSMP FDA FDAAA GCP Gold Book HIPPA HSC IACUC IDE IIT IND IRB LOI NIH NLM OHRP ORIC OSP PI SAE SOC TBD TBE TBN WVCTSI

Abbreviations
Adverse Event College of American Pathologists Confidentiality Disclosure Agreements Collaborative IRB Training Initiative Clinical Laboratory Improvement Amendments Conflict of Interest Case Report Form(s) Clinical Trials Research Unit Clinical Trials Working Group Curriculum Vitae Data Monitoring Committee Data Safety Monitoring Board Data and Safety Monitoring Plan Food and Drug Administration Food and Drug Administration Amendment Act of 2007 Good Clinical Practice WVCTSI Operations Manual Health Insurance Portability and Accountability Act of 1996 Health Sciences Center Institutional Animal Care and Use Committee Investigational Device Exemption Investigator Initiated Trial Investigational New Drug Institutional Review Board Letter of Intent National Institutes of Health National Library of Medicine Office of Human Research Protection Office of Research Integrity and Compliance Office of Sponsored Programs Principal Investigator Serious Adverse Event Standard of Care To Be Determined To Be Established To Be Named West Virginia Clinical and Translational Science Institute

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I. Clinical Trials Working Group (CTWG)
The WVCTSI Director, the Vice President of Research and Graduate Studies, and the WVCTSI Assistant Director of Operations work closely with the Director of the CTRU. The CTWG Chairman is charged with establishing and maintaining CTRU research infrastructure, integration, and interfaces to support clinical trials and population research missions. The CTWG meets on a bimonthly basis and is composed of faculty and hospital leaders throughout the Health Sciences Center. The CTWG is committed to leading, building, and providing suitable resources for WVCTSI investigators to conduct highly interactive clinical trial and population research projects. In addition, the CTWG also facilitates research collaborations across partner institutions. In the WVCTSI, each partner institution organizes and centralizes their participant-oriented research activities under the CTWG umbrella to increase efficiency and provide a mechanism for regular and ongoing information about studies, investigators, and personnel. See Appendix 1 for a list of members.
Purpose
The main function of the CTWG is protocol review and monitoring. The CTWG is responsible for scientific review of investigator-initiated protocols. More specifically, CTWG is established to accomplish the following:
• To advise the WVU Institutional Review Board on the scientific merit of proposed protocols.
• To establish priority ranking for protocols.
• To ensure that each clinical trial or proposed study has an appropriate statistical section.
• To ensure that the data to be collected are appropriate to the study’s goals.
• To monitor the progress of WVCTSI protocols.
• To activate approved research protocols.
• To recommend protocol closure to the appropriate Department/School leadership.
Criteria for Selection of CTWG Membership
The Director of Clinical Research appoints members of the CTWG. Ad Hoc members are added as dictated by the protocol therapeutic area. Clinical Trials Working group includes a balance of senior clinical investigators and new clinical investigators so as to foster the development of new researchers. Additional reviewers are asked by the CTWG to comment on specific protocols and to assist in the review of protocols in their area of expertise, as needed.
CTWG Expertise and Charge
The CTWG has sufficient breadth of expertise to allow objective and critical scientific review of all types of therapeutic, non-therapeutic and investigator-initiated clinical trials. The Committee includes experts from each of the respective sub-specialties that include: pediatrics, internal medicine, nursing, pharmacy, community medicine, behavioral sciences, laboratory correlative studies, biostatistics and patient advocacy. At time of the review, a representative (preferably the PI) for the trial participates in the discussion, but is not involved in the review process itself. Often, trials

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are conditionally approved pending clarification of certain scientific elements. The CTWG is charged with review of the scientific rationale for the trial, establishing the priority relative to other clinical trials, and providing input and review regarding the objectives and rationale of the study, the study design including assessment of drug schedule, drug dose sequence plus escalation and de-escalation, and laboratory correlative studies, biostatistical input of endpoints and sample size, feasibility of both accrual and patient tolerance and completion of laboratory correlative studies.
Protocol Routing and Activation
Once the protocol has been reviewed and approved by the CTWG, the Clinical Trials Research Unit (CTRU) Regulatory Office is notified that the protocol is allowed to be submitted to the WVU IRB. If other approvals are required, such as those for cell and gene therapy protocols, the appropriate additional committee is apprised such as the Biosafety Committee, Radiation Safety Committee, etc. Simultaneously, Clinical Trials Research Unit (CTRU) coordinates other necessary documents that allow protocol activation. All protocols that involve patients placed on pharmacokinetic studies, research biopsies, etc., are reviewed and coordinated with the CTRU. Once each of the components of protocol approvals has been completed, this is reviewed by HSC administration and the protocol is signed off and activated by the Director for Clinical Research.
Selection Criteria for CTWG Membership and Interactions
Members of the CTWG are appointed by the Director for Clinical Research with consultation with the HSC Chancellor for a renewable 3-year term. Members are expected to participate in the semimonthly committee meeting and provide focused expertise as needed in protocol review. In rare instances, the CTWG may invite an outside reviewer or convene an ad hoc committee to assist with the review of a protocol or other matter that falls outside the committee’s expertise or to address a scientific issue that may entail a potential conflict.
Guidelines for Operation
The CTWG meets semi-monthly. The meeting is chaired on a rotating basis by the Chair and coChairs; each is responsible for sign-off of final minutes for the appropriate session chaired. The CTWG Chair is responsible for overall coordination of the meeting and responding to or directing any inquiries. The assigned meeting Chair and co- Chair develop the meeting agenda, which is distributed a minimum of 3 days before each scheduled meeting. The Committee considers new concepts (LOIs) presented by individual investigators, reviews new protocols, and monitors the progress of active studies.

II. Protocol Review and Monitoring
Emphasis of protocol review and monitoring is placed on review of investigator-initiated institutional trials and investigations. Of greatest importance is the assistance the Clinical Trials Working Group provides investigators in the development of concepts that lead to successful activation of novel clinical research protocols. Guidance is also provided to those studies, which are prevention and behavioral intervention oriented. Investigators are encouraged to bring new therapeutics concepts or letters of intent to the CTWG for review. By the time these trials are reviewed, bio-statistical input has been provided through the WVCTSI Clinical Research Design, Epidemiology & Biostatistics Core

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Facility faculty, and study coordinators have participated in the logistical operations development. The department Chair and/or Section Chief will have reviewed the concept or LOI for the availability of patients and for overlap in prioritization relative to other active clinical trials.
A. Protocol Concepts/LOIs Review
Before development of a formal protocol, investigators are encouraged to present the objectives of the proposed trial in the form of a concept/letter of intent (LOI) for review by the CTWG. The proposed trial will be discussed with the investigator present, from the following points of view: 1) scientific merit; 2) statistical methodology; 3) relationship to ongoing protocols; and 4) accrual goals. The potential funding source(s) for any particular concept/LOI is also identified (e.g., industry sponsor, etc.). Investigator-initiated clinical investigation is given highest priority by CTWG, since this is the primary level of physician investigator-initiated clinical investigation and provides an important venue to mentor new and junior investigators. Priority is also given to WVCTSI clinician scientists, scholars and pilot awardees. No formal action is taken by the CTWG on concept presentations. Formal LOI submissions are, however, fully reviewed and acted upon by the Committee.
B. Review of New Protocols
A CTRU service application, reviewer, statistician and study coordinator sign-off sheets, are used to facilitate the review process, see Appendix 8.
Prior to the CTWG review, two members are designated by the Chair or co-Chair to review each protocol. The CTWG review includes a biostatistician and pharmacy reviewers (as applicable). In general, the reviewers will be representative of the discipline appropriate for the protocol under review. The CTWG will make every effort to avoid assigning potential co-investigators as reviewers. The reviewers receive a complete protocol, informed consent document, and sign-off sheets 5 days prior to the meeting.
The Committee evaluates the scientific merit of proposed protocols, appropriateness of the target population, and appropriateness of patient care. The CTWG ensures that each clinical trial has an appropriate statistical section and a realistic accrual goal. The reviewing statistician is responsible for statistical sign-off.
For industry sponsored and multicenter nationally funded studies, the assigned study coordinator is responsible for logistical review and presenting the study at a convened CTWG meeting. The CTWG has the opportunity to ask questions and to assure that the study is feasible, CTRU resources are available and costs are covered by the sponsor. The PI is usually not required to attend this meeting, but is free to request attendance on a case by case basis. These studies are usually not subject to scientific review.
See CTRU protocol submission and activation schema on page 19.

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Scientific Score and CTWG Recommendations
The CTWG assigns a scientific score, range 1.0 to 5.0: 5-Outstanding, 4- Excellent, 3 - Good, 2 Acceptable, 1 - Not Scientifically Meritorious.
In addition the protocol is given a probability of funding score: 5 – High, 3 -Medium, 1- Low.
Overall score is the product of the two scores. An overall score of greater than 10 would be considered meritorious and score of 25 is the highest possible overall score.
CTWG may take one of the following actions based upon the recommendation of the reviewers: the protocol may be approved; approved pending clarification or incorporation of committee recommendations; deferred for major revision or clarification; or not approved. Action is based on the majority of members present at the meeting.
The CTWG’s recommendations are provided to the Director for Clinical Research, and the WVU IRB. Written recommendations are given to the investigator(s). The CTWG will review deferred/disapproved protocols after modification, and if found acceptable, the approval is forwarded to the IRB for consideration.

C. Guidelines for Initiation of an Amendment
All changes in an investigator-initiated protocol are submitted to the CTRU and the CTWG in the form of an amendment and signed by the principal investigator at the time of IRB submission. Most of these are administratively reviewed. However, any major changes in the treatment intervention, increased risk, or toxicity reporting are reviewed by the full committee. All amendments are submitted to the IRB after CTWG review.

III. Investigator Initiated Protocol Development

A. Protocol Development Guidelines
A clinical trial is designed to answer a specific question or set of related scientific questions. Having a clear hypothesis and related set of scientific questions is essential to design the clinical trial appropriately and ensure that the experimental plan is well suited to address the questions.
1Two tips when formulating a research question and/or hypothesis:
1. It is very important that it meets the following criteria: Feasible, Interesting, Novel, Ethical and Relevant (FINER)
2. It should be as informative as possible so it should include the description of the: Population, Intervention, Comparison group, Outcome (PICO).
1 Guide to Clinical Research At USC: pages 50-58, October 2013

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Clinical Research Operations Manual