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Institutional Data and Safety Monitoring Plan
For further information concerning this do...
I. Monitoring the Progress of Trials and the Safety of Participants…………………. 3
I.A. Prior to Protocol Activation……………………………...
Data and Safety Monitoring Plan (DSMP)
This document describes the institutional data and safety monitoring ...
responsibility for the protocol. A Site PI is assigned to oversee the conduct of the trial at each
individual performance ...
Any member who has one of the conflicts of interest must inform the committee and excuse
himself or herself from voting on...
the IRB per the process outlined below. Adverse Events are also reported to the sponsors and
regulatory agencies as define...
Phase III Trials
All DF/HCC initiated and/or NCI sponsored phase III trials (not including Cooperative Groups) require
Medical Chief of Staff, DFCI
Chief, Director Hematology Oncology, MGH
DF/PCC Vice-President for Clinical Program Developme...
B. Quality Assurance Office for Clinical Trials (QACT)
The QACT is charged with creating a standardized management system ...
All auditors report to the Quality Assurance Officer for DF/HCC to minimize the potential for institutional
bias or confli...
• A database is maintained by the Audit Managers to provide statistical information that can be used
to improve the audit ...
D. Clinical Trials Education Office (CTEO):
The Clinical Trials Education Office plays a major role in the Human Research ...
management. Topics covered in this session include source documents, regulatory binders,
research files and case report fo...
changing or terminating the trial. The DSMB provides a summary of the board findings to the IRB,
CLINPOC and the principal...
The study team should implement recommendations from the DSMB expeditiously. When requested by
the DSMB, the protocol PI w...
nursing, pharmacy, legal representatives, a medical ethicist, and lay members from the community and
across DF/HCC who hav...
feasibility of the research plan, the capability of the research team to conduct the trial in a timely fashion,
and whethe...
A. DFCI IRB Requirements and Reporting:
Unanticipated risks are sometimes discovered during the course of research. Inform...
• Grade 2 (moderate) and Grade 3 (serious) Events – Only events that are Unexpected and
Possibly, Probably or Definitely R...
hospitalization may be considered a serious adverse drug experience when, based upon appropriate
medical judgment, they ma...
data or data quality are referred either to the auditing program or to CLINPOC, depending on the
circumstances. Problems w...
Revised February 2008
Clinical Trials Support
Protocol Activation and Management
Appendix I
Revised February 2008
Clinical Trials Process
Note: Detailed process steps may vary according to specific study and fundin...
Revised February 2008
- Early protocol review
- Data Collection Forms design
- Set up and maintain...
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  1. 1. DANA-FARBER/HARVARD CANCER CENTER Institutional Data and Safety Monitoring Plan For further information concerning this document, please contact: Jane Russell Alyssa K. DellaCroce, MPH CCRP Quality Assurance Officer for Clinical Trials Assistant Director, QACT Dana-Farber Cancer Institute Dana-Farber Cancer Institute 44 Binney Street (OS-200) 44 Binney Street (OS200) Boston, MA 02115 Boston, MA 02115 Tel: 617-632-3764 Tel: 617-632-3731 Email: Email: Table of Contents Revised February 2008 1
  2. 2. I. Monitoring the Progress of Trials and the Safety of Participants…………………. 3 I.A. Prior to Protocol Activation…………………………………………………… 3 I.B. Post Activation and Continual Monitoring……………………………………. 5 I.C. Monitoring Requirements for Clinical Trials…………………………………. 6 II. Institutional Oversight of Clinical Trials…………………………………………… 7 II.A. Clinical Investigations Policy and Oversight Committee…………………….. 7 II.B. Quality Assurance Office for Clinical trials………………………………….. 9 II.C. Office for Protection of Research Subjects……………………………………. 11 II.D. Clinical Trial Education Office………………………………………………… 11 II.E. Research Pharmacy…………………………………………………………… 13 II.F. Data and Safety Monitoring Board…………………………………………… 13 II.G. Data and Safety Monitoring Committee……………………………………… 15 II.H. Institutional Review Board…………………………………………………… 15 II.I. Scientific Review Committee………………………………………………… 16 II.J. Pediatric Scientific Review Committee………………………………………. 17 II.K Connell & O’Reilly Families Cell Manipulation Core Facility (CMCF)and DFCI Clinical Research Laboratory 17 III. Assuring Compliance with Requirements for Reporting Adverse Events ………… 17 III.A. Institutional Review Board Requirements and Notification………………… 18 III.B. IND Safety Reports………………………………………………………….. 18 III.C. Adverse Event reporting Guidelines………………………………………… 18 III.D. Definitions…………………………………………………………………… 19 IV. Notification of NCI Regarding Temporary or Permanent Suspension of a Funded Clinical Trial…………………………………………….. 20 V. Assuring Data Accuracy and Protocol Compliance……………………………….. 20 Appendix 1. Dana-Farber/Harvard Cancer Center (DF/HCC) Clinical Trials System Appendix 2. DF/HCC Clinical Trial Process Appendix 3. DF/HCC Clinical Trial Study Team Dana-Farber/Harvard Cancer Center (DF/HCC) Revised February 2008 2
  3. 3. Data and Safety Monitoring Plan (DSMP) Introduction: This document describes the institutional data and safety monitoring plan for cancer clinical trials that are performed through the Dana-Farber/Harvard Cancer Center (DF/HCC) comprised of Dana-Farber Cancer Institute (DFCI), Brigham and Women’s Hospital (BWH), Massachusetts General Hospital (MGH), Children’s Hospital (CH), Beth Israel Deaconess Medical Center (BIDMC), the Harvard Medical School (HMS) and the Harvard School of Public Health (HSPH). Therapeutic and non-therapeutic research protocols related to cancer within DF/HCC are performed under the oversight of the DFCI Institutional Review Board (IRB). See Appendix I, which describes the overall structure of the clinical trial support function. For the purposes of this document the operational definition of a clinical trial as defined by the National Cancer Institute (NCI) is: “a prospective study involving human subjects designed to answer specific questions about the effects or impact of particular biomedical or behavioral interventions; these may include drugs, treatments, devices, or behavioral or nutritional strategies. Participants in these trials may be patients with cancer or people without a diagnosis of cancer but at risk for it.” Further clarification of this definition can be found at: Overall DSMP for all DF/HCC Clinical Trials: I. MONITORING THE PROGRESS OF TRIALS AND THE SAFETY OF PARTICPANTS DF/HCC trials are monitored in many ways through development, review and performance throughout the lifecycle of the research protocol. Appendix II describes the clinical trials process. The following narrative describes the protocol monitoring process: before activation; and after activation; including additional or modified requirements for Pilot, Phase I, Phase II, Gene Transfer, behavioral trials and multi- center trials and oversight. All oncology trials in DF/HCC go through a central protocol review and monitoring process. This includes: Scientific Review Committees (SRCs), initial and continuing IRB review, central eligibility checking and protocol participant registration, Internal Auditing, Accrual Monitoring, and oversight by the Clinical Investigations Policy and Oversight Committee (CLINPOC). Individuals from DFCI, MGH, BWH, CH and BIDMC are members of the committees involved in the review process. All Harvard Medical School (HMS) clinical investigators have individual hospital appointments in addition to their Medical School appointments, and initiate their oncology clinical studies through one of DF/HCC Disease Programs. The Disease Programs have representation from participating clinical institutions. All protocols with cancer as the primary disease fall under the jurisdiction of the DFCI IRB. A. PRIOR TO PROTOCOL ACTIVATION: • Disease Programs include representation from all participating hospitals. They review and approve all new protocols for feasibility and determine priority within the Disease Program. Protocol documents include a protocol specific monitoring plan and should include reference to the DF/HCC Data and Safety Monitoring Plan (DSMP). • The Scientific Review Committees (SRC) reviews for scientific merit and feasibility the protocols referred by the Disease Programs. An Adult SRC and a Pediatric SRC are involved in this comprehensive review process. Each committee is made up of senior staff with expertise necessary to make the scientific decisions. The Overall Principal Investigator (PI) is the person with ultimate Revised February 2008 3
  4. 4. responsibility for the protocol. A Site PI is assigned to oversee the conduct of the trial at each individual performance site (location). Six IRB panels registered with Office of Human Research Protection (OHRP) Panel A, B, C, D E and F review and approve all new and continuing protocols focusing on risk vs. benefit for the participants involved in research, and assure their protection to the maximum extent possible. The above review processes include multi-modality physicians, nurses, pharmacists, lay/community members, biostatisticians, and administrative staff who review their various areas of expertise for the committees. The panels meet the regulatory requirements of composition. • The Office for Protection of Research Subjects (OPRS) administrates manages the SRCs and IRBs for DF/HCC and provides all documentation for actions by the SRCs and IRBs. All required regulatory documentation is centrally maintained in this office. (The Director of OPRS, reports directly to the DFCI Senior Vice President for Research). • The most recent version of the protocol, consent document, eligibility checklist, and disease program priority lists are maintained by the OPRS on the computerized Oncology Protocol System (OncPro) which is available to Investigators and all research staff at DFCI, BWH, MGH, CH, BIDMC, and OncPro authorized network affiliates. The Overall PI or designated research team member is responsible for keeping sites that do not currently have access to the online system updated on changes. • The Data and Safety Monitoring Board (DSMB) review is required for all Phase III DF/HCC initiated trials, which do not have an external DSMB established. Protocols are identified prior to activation. The DSMB meets twice a year to review accrual, toxicity, response and reporting information. This committee is chaired by a medical oncologist from outside of DF/HCC and has external and internal representation. Information that raises any questions about patient safety or protocol performance is addressed with the Principal Investigator, statistician and study team members. The DSMB submits a summary of the meeting and recommendations to the IRB and CLINPOC. The DSMB process is described in detail in the Oversight Section of this document • The Data and Safety Monitoring Committee (DSMC) was formed to review all high risk Pilot, Phase I and Phase II protocols and meets quarterly to allow frequent monitoring and reviews of these protocols. Protocols are considered high risk if they are the first time in humans, multi- center, PI initiated or gene transfer trials. The DSMC Chairperson and the QACT select protocols requiring review. The DSMC consists of DF/HCC faculty and research staff. The process is detailed in the Oversight Section of this document • Physicians and staff are responsible for following the Harvard Conflict of Interest Rules for avoiding conflicts of interest. They are required to report annually to Harvard University any financial interests that could have real or apparent conflict with their research, regardless of the source of research funding. The following statement appears on every IRB and SRC agenda: “IRB members are required to recuse themselves from voting on protocols if: 1) they are involved in conducting, evaluating, or “participating” in the research, as defined in the HMS Policy on conflict of interest, or 2) they have “significant financial interests” (i) that would reasonably be affected by the research for which the committee approval is sought, and/or (ii) in entities whose financial interests would reasonably appear to be affected by the research.” “Significant financial interest” means (i) any salary or other payment for service, royalties, and any other payments from a company that in the aggregate exceeds $10,000 per year, (ii.) any equity interest in a company, except for an interest that does not exceed $10,000 in a publicly held company, (iii) any financial arrangement in which compensation from the company could be higher for a favorable outcome than for an unfavorable outcome and (iv) any proprietary or other financial interest in the tested product. The “significant financial interest” includes the aggregate interest held by the committee member, his/her spouse, dependent children and/or any associated entity. Revised February 2008 4
  5. 5. Any member who has one of the conflicts of interest must inform the committee and excuse himself or herself from voting on the protocol(s) in question. There may be other circumstances that create a conflict of interest and warrant recusal from voting (for example, having a supervisory role over an investigator), and such circumstances should also be disclosed. All conflicts will be noted and recorded in the minutes of each meeting along with the above statement. Each protocol application also requires that investigators identify any conflict of interest that may exist relating to the protocol or sponsor. • Training in regulatory compliance is required and documented for all DF/HCC investigators and research staff. The Collaborative IRB Training Initiative (CITI) is currently used to comply with the requirements for Human Subjects Protection Training of all research staff. Online documentation of policies and procedures for conducting DF/HCC clinical trials is available through the Clinical Research Operations website and the Guide to Human Research Activities. Additional training coordinated by the Clinical Trials Education Office (CTEO) is offered monthly for investigators and research staff from all sites. A listserv program is used to notify staff of new policies and procedures for protection of human subjects or announcements relating to management and conduct of clinical trials. B. POST ACTIVATION AND CONTINUAL MONITORING: • All participants are enrolled in clinical trials through the Quality Assurance Office for Clinical Trials (QACT). Eligibility checklists are reviewed and approved by the Registrar prior to registration. Signed consent forms are verified for appropriate signatures and proper version. • The pharmacy department checks that a participant is formally enrolled on the research protocol before dispensing investigational agents. The electronic Chemo Order Entry System (COE) is in place at MGH, BWH, DFCI and CH. The system automatically checks subject registration and a protocol template is automatically provided when the physician begins writing the order for a protocol participant. These systems were created over ten years ago as a major move toward increasing patient safety and regulatory compliance. • Amendments to clinical trials are reviewed by the DFCI IRB and processed by the OPRS with the appropriate notification and documentation. • Continuing Review occurs at least annually for all protocols under the jurisdiction of the DFCI IRB. This review focuses on a review of the risks, benefits, adverse event reports and progress of the project. • The IRB determines when it is necessary to inform participants of any new findings that reveal additional risk or information that may alter their willingness to participate in the trial. • The study team for DF/HCC clinical trials consists of the Overall PI who holds primary responsibility for monitoring the participants on their protocol, Site PI(s), Research Nurses, Clinical Research Coordinators, QACT Data Analysts and Biostatisticians, among others. The study team assists the PI in managing the protocol. (See Appendix III). The team is responsible for knowing which participants are on the protocol, the adverse events that occur, the general progress of the study, and data collection. All members of the team work together to ensure subject safety and data accuracy. Study teams meet frequently to review their protocols and discuss the status of the participants being treated on their studies. Some teams meet as often as weekly depending on the complexity of the trial. The study team reports Adverse Events (AE) to Revised February 2008 5
  6. 6. the IRB per the process outlined below. Adverse Events are also reported to the sponsors and regulatory agencies as defined in the AE Reporting Guidelines. • Panel C of the IRB reviews Serious Adverse Events (SAE) reports and Continuing Reviews. This committee closely scrutinizes these reports and summary listing of SAE reports per protocol. When there is any question of safety, the PI is questioned further and more information is obtained. When action is needed, the committee may propose and carry out any action deemed necessary. These actions relate to all participating institutions. • DF/HCC clinical trials are subject to internal auditing across all Disease Programs per the internal auditing policies and procedures. The DF/HCC Internal Audit Program has three full time auditors who report to the Quality Assurance Officer for Clinical Trials. Approximately sixty protocols per year are audited. The auditors review from five to six records for each protocol. Subject’s records audited may be from any of the DF/HCC affiliate hospitals. The audit process is outlined in detail in the Oversight Section of this document • Protocols are reviewed twice a year for slow or inadequate accrual by the QACT. Reports are submitted to a subcommittee of CLINPOC to recommend appropriate action. Fast accruing protocols are also monitored to be sure they are proceeding in a safe and effective way. • Phase I dose escalations are continuously monitored by the QACT to be sure that the appropriate number of participants are entered at each dose level per protocol design. • Data for many NCI-sponsored and DF/HCC-initiated trials are computerized through a central Quality Assurance Office for Clinical Trials (QACT). The Case Report Forms (CRFs) are designed by the Data Analysts in the QACT with input from the study team. Data collected by individual Study Coordinators are submitted to the QACT on CRFs for review, computerization, quality control, and preparation for analysis. Reports are programmed to keep the study team updated on study progress. The data analysts initiate QACT monitoring of PI-initiated trial data. They quality assure the CRFs, review the status of computerized data in the clinical research database, educate study team members on data collection methods and accurate reporting of study data on CRFs, and quality control the data collection process for accuracy and efficiency. Good Clinical Practice (GCP) methods are followed including the practice of correcting data forms by striking through the error, initialing and dating the change. In the fall of 2005, conversion to an electronic data capture system (Phase Forward - Inform) began. This system is in a phased implementation process by disease programs. C. DF/HCC MONITORING REQUIREMENTS FOR CLINICAL TRIALS: Phase I Trials All DF/HCC-initiated Phase I trials testing new therapies in pediatric populations require review by the central Data and Safety Monitoring Committee (DSMC). DF/HCC-initiated Phase I trials where therapy is being tested First-In-Man and where high levels/grades of toxicity are expected will also require review by the DSMC. Investigators conduct continuous reviews of data and subject safety at their regular Phase I/Disease Group meetings where the results of each participants’ treatment are discussed and the discussion is documented in the minutes. The discussions include for each dose level: the number of participants, any significant toxicities as described in the protocol, any dose adjustments, and all responses observed. Phase I/II and Phase II Trials All high-risk Phase I/II and Phase II trials are reviewed by the DSMC including gene transfer protocols. Revised February 2008 6
  7. 7. Phase III Trials All DF/HCC initiated and/or NCI sponsored phase III trials (not including Cooperative Groups) require review by the DF/HCC Data and Safety Monitoring Board (DSMB), if an external DSMB is not established. Behavioral Clinical Trials DF/HCC behavioral trials that are identified as having a high degree of risk require a DSMP and review by either the DSMB or DSMC. Multi-Center DF/HCC-Initiated Trials DF/HCC initiated multi-center trials, which include institutions outside of the DF/HCC, may be monitored by the Internal Auditing Program. Data are collected on the Case Report Forms (CRFs) for each research protocol. Data are computerized in the QACT and undergo the same quality control procedures as for other protocols. These protocols are monitored by either the DSMB or the DSMC. II. INSTITUTIONAL OVERSIGHT OF CLINICAL TRIALS (Committees and Offices) A. Clinical Investigations Policy and Oversight Committee (CLINPOC) The Clinical Investigations Policy and Oversight Committee (CLINPOC) is a committee that oversees the clinical research process at DF/HCC. An important function of CLINPOC is its role as the committee responsible for the review of audits of ongoing clinical trials, monitoring of accrual and performance and, compliance with federal, NCI, and institutional regulations related to clinical research. The Dana- Farber/Harvard Cancer Center (DF/HCC) is committed to ensuring high quality clinical research standards. DF/HCC institutions have delegated authority, by written agreement, to CLINPOC, a Dana- Farber Cancer Institute Committee, to oversee the clinical research process for cancer protocols. The purpose of CLINPOC is the oversight of the DF/HCC clinical research process and development of policies and procedures to ensure subject safety and high quality clinical research. As dictated by the Medical Staff Bylaws, the President of DFCI appoints the CLINPOC membership and the Chair. Each DF/HCC participating organization has a written agreement with DFCI delegating oncology clinical trial oversight to the DFCI clinical trials review system. Each agreement identifies a responsible person (or committee) at the institution to whom CLINPOC should communicate relevant concerns regarding problems in compliance, trial performance, or scientific misconduct. This person is also responsible for reporting back to CLINPOC any actions taken to address the concerns. [For example, at DFCI, CLINPOC reports to the Medical Staff Executive Committee (MSEC). MSEC in turn reports to the Joint Quality Improvement and Risk Management Committee, which is a subcommittee of the DFCI Board of Trustees.] Summary reports of CLINPOC concerns and resulting actions will be sent, quarterly and annually, to the DF/HCC Clinical Sciences Coordinating Committee (CSCC), DF/HCC Executive Committee (EC), and the appropriate institutional- individuals or committees noted above. CLINPOC generally meets on the fourth Thursday of each month. CLINPOC members vote on any change in meeting date. The auditing and monitoring segment of the meeting occurs first, followed by the clinical policy segment. The QACT coordinates this meeting and is responsible for maintaining the records. The minutes will be in two sections to reflect the segment of the meeting that has peer-review protection. CLINPOC members include representatives from committees and departments shown below: Chair, Department of Adult Oncology, DFCI/BWH (CLINPOC Chair) Chair, Department of Biostatistics (CLINPOC Assistant Chair) Senior Vice President for Research, DFCI Revised February 2008 7
  8. 8. Medical Chief of Staff, DFCI Chief, Director Hematology Oncology, MGH DF/PCC Vice-President for Clinical Program Development Director of Clinical Trials Support, DF/PCC Chair, Pediatric Scientific Review Committee, DFCI/CH Clinical Director, Pediatric Oncology, DFCI/CH Chief, Hematology/Oncology Division, BIDMC Co-Director of Sarcoma Clinic/Surgical Oncology, BWH Chair, Department of Radiation Oncology, DFCI/BWH Chair, Institutional Review Board, DFCI Chair, Quality of Life Committee, DFCI Chief Operations Officer, DFCI Director, Nursing Education and Clinical Practice, DFCI Pediatric Nurse Practitioner, DFCI Director of Pharmacy Director, Office for Protection of Research Subjects QA Officer for Clinical Trials Director, Risk Management Clinical Trial Audit Managers Director, Clinical Trials Education Office In January of 2004, three subcommittees of CLINPOC were formally designated within CLINPOC: 1. Operations Subcommittee: This committee meets weekly and reviews operations relating to clinical research and manages problems that are observed. Members of this subcommittee represent the institutions, Pharmacy, Nursing, Information Services, data management, and others. The Director of Clinical Trials Support assigns membership to this subcommittee. 2. Accrual Monitoring Subcommittee: This committee identifies slow-accruing protocols within each Disease Program biannually. If a protocol is identified as slow accruing, the PI must write a letter of justification and a plan for increasing accrual to the committee. The subcommittee reviews the letter, and a determination is made if the study should remain open longer or closed. The subcommittee keeps CLINPOC apprised of its actions, and a study is not closed for slow accrual until reviewed by CLINPOC. The QACT also monitors protocols for rapid accrual on a monthly basis. The study team of a rapid accruing trial, the DSMC or DSMB and the Accrual Monitoring Subcommittee are notified. The Chair of CLINPOC assigns membership to this subcommittee. 3. Audit Review Subcommittee: The Audit Review Subcommittee makes recommendations to CLINPOC regarding significant findings in audit reports. This subcommittee was developed to ensure timely reviews and allow CLINPOC to spend more time at their regular meetings for policy issues. This subcommittee consists of Medical Oncologists, Pharmacy, Nursing, and the Internal Audit Managers. The DFCI President or his delegate assigns membership to this subcommittee. The three subcommittees meet outside of the regular CLINPOC meetings. CLINPOC communicates with the investigators and others as necessary to resolve issues noted in the oversight process and has the authority to enforce the policy standards it develops. CLINPOC reviews all new policies relating to clinical research for approval. The committee may seek advice from the CSCC or MSEC. Documentation of the CLINPOC sessions is maintained by the QACT. Revised February 2008 8
  9. 9. B. Quality Assurance Office for Clinical Trials (QACT) The QACT is charged with creating a standardized management system for clinical trials data. The QACT is responsible for the protocol registration system, eligibility review, accrual monitoring, case report form design and implementation, computerization of data, data integrity, protocol auditing and monitoring for compliance and quality assurance of all clinical trial processes within DF/HCC. Additionally, the QACT is responsible for the administrative management of the institutional DSMB (Phase III) and DSMC (Pilot/Phase I and II) for DF/HCC, CLINPOC and the CLINPOC Subcommittees. QACT Functions: All of the above functions have been discussed throughout this document and therefore will not be highlighted here with the exception of Internal Auditing. INTERNAL PROTOCOL AUDITING: The goals of the QACT auditing process are: • To ensure and confirm ongoing clinical protocol compliance based on DF/HCC established IRB guidelines, policies and procedures, and in accordance with federal regulations. • To educate the clinical research staff to promote greater awareness and understanding of policies, procedures and objectives, and to increase efficiency and consistency in the clinical trial process at DF/HCC. • To detect “system” errors in the DF/HCC policies and procedures that leads to non-compliance or risk to participants. This process allows corrective actions to be implemented in a consistent manner as well as meet changing needs across all participating institutions. A major violation is defined as a violation that significantly alters the clinical effectiveness of the treatment or the evaluation of its toxicity. Minor violations occur when the protocol is not followed exactly, but the data are usable and valid. The audits are rated on the following performance scale. 1. Exceptional Evidence of superior source documentation, data quality, protocol and regulatory compliance. No response required. 2. Satisfactory Few minor deviations noted. No response required. 3. Acceptable, needs follow-up Requires follow-up for the major violation(s) listed. 4. Unacceptable Requires (at a minimum) a written corrective plan and interim re-audit with re-audit interval clearly specified in the audit report. Any major violation observed in a protocol audit is considered serious and requires corrective action or a written explanation from the Overall Principal Investigator. All audit results are maintained in the DF/HCC Audit Summary Database. This database is used to evaluate the program and as a continuous quality improvement tool. CLINPOC created a subcommittee in January of 2004 to review audit reports and make recommendations to the larger committee regarding significant findings. This subcommittee was developed to ensure timely reviews and allow CLINPOC to spend more time at their regular meetings for policy issues. The audit subcommittee consists of medical oncologists, pharmacy, nursing and the internal audit managers. Revised February 2008 9
  10. 10. All auditors report to the Quality Assurance Officer for DF/HCC to minimize the potential for institutional bias or conflict of interest inherent between clinical investigators and audit functions at the same institution. The auditing process for maintaining quality and improving the performance of clinical trials at DF/HCC is presented at regular education and training workshops organized by the Clinical Trials Education Office for both new physicians and research staff. DF/HCC auditors audit approximately 60 protocols per year. All active DF/HCC protocols are eligible for audit, including those protocols sponsored by NCI, pharmaceutical industry or other sponsors. The Internal Audit Managers select protocols from a list of eligible studies and disease sites. The auditors attempt to distribute the audits evenly among the various Disease Programs and treatment modalities. Audits are performed using predefined procedures and report templates. The audit process begins with the selection of a protocol to audit. The Internal Audit Manager selects protocols according to set criteria (disease site schedule, prioritization within the disease site, new investigators, and number of participants accrued). The Internal Audit Manager will inform the Overall and Site PIs and their appropriate study research staff of the protocol that will be audited at least one month in advance, and schedules the exit interview with the PI and his/her study team. Each PI to be audited will receive the following information: • A letter listing the information that will be audited and the logistics of the day, such as time, date and place. • A listing of the participants to be audited. • A copy of the DF/HCC Clinical Trials Audit Manual. The process continues as follows: • The Internal Audit Manager will select five to six subjects to audit from a protocol. Subject selection is impartial; however, the auditor will take into account the number of affiliate participants enrolled in the study and treatment arms. • The selected participants’ records and protocol regulatory documents will be reviewed • During an audit, physicians and/or clinical staff are available to assist the auditor as needed. • The Audit Manager will complete an Audit Review Form for each participant during the audit to assess performance of data collection and protocol compliance. • The Audit Manager will summarize the results at the end of the audit and verbally communicate them to the study team. The exit interview will be conducted by the Audit Manager with the Principal Investigator (PI) and the study staff and usually takes place within 72 hours of the audit completion. During the exit interview, the PI responds to any recommendations or questions that have arisen during the audit. • The Internal Audit Manager will prepare a written final audit report within one week of the exit interview. The Overall PI will be asked to sign acceptance of the audit report and reply with corrective action plans as needed. • CLINPOC’s Audit Subcommittee will review the audit reports at the next scheduled meeting to determine if any further action is required. Timeframes listed here are ideal. • No follow-up will be required if the audit is evaluated as Exceptional or Satisfactory. However, CLINPOC will require follow-up if the audited protocol is evaluated to be Acceptable, Needs Follow-up or Unacceptable. • Follow-up may involve implementation of new procedures regarding individual protocol performance or system-wide changes within DF/HCC. Other follow-up options may include a re- audit of the protocol in question, auditing a related protocol if the previously audited protocol is closed, or closure or temporary closure of the protocol are also follow-up options. Revised February 2008 10
  11. 11. • A database is maintained by the Audit Managers to provide statistical information that can be used to improve the audit process and to support quality improvement initiatives. This information is presented to CLINPOC members regularly. • The reference manual entitled The Guide to Human Research Activities describes the audit process and is readily available online on the CTEO website. DATABASE MANAGEMENT AND MONITORING: The QACT Data Analysts manage the computerized databases for DF/HCC initiated in-house clinical trials including DFCI, BWH, MGH, and BIDMC trials. The Data Analysts: • Design data collection forms for clinical trials • Initiate, maintain and quality control the computerized data for the projects • Maintain documentation for database, and integrity of the database • Provide quality assurance on data collection methods • Monitor conduct of the clinical trials • Prepare data for analysis • Produce regular reports requesting missing data and updates provide program reports for the study teams • Assist in training of research staff in data collection methods. The QACT Data Analysts interact with the study team including, the Principal Investigators, research Nurses, Study Coordinators, and Biostatisticians for quality data assurance and management. An additional process for monitoring was implemented in 2002 to enhance the quality of the data collected on PI initiated trials. This process compliments the auditing program already in place, but focuses on data accuracy versus the protocol compliance issues that are addressed in audits. Data completion and database accuracy are reviewed. This creates educational opportunities for study coordinators. New protocols and new study coordinators are targeted after the first three patients have been entered on clinical trials. A QACT Data Analyst III serves as the data monitor and reviews the medical record, the Case Report Forms and the QACT Database to confirm that the data collection is accurate and that it has been accurately recorded in the database. Any problems are discussed with the study team and corrected appropriately. This checking of the source documentation is in addition to the extensive QA process that already occurs of all data processed through the QACT. Summary results are reported to CLINPOC biannually. C. Office for the Protection of Research Subjects (OPRS): The OPRS provides administrative management support and regulatory guidance to the review committees that protect research subjects. They also provide support to the investigators and the research teams. OPRS is responsible for the training and education of IRB members. This office coordinates the IRB and SRC committees and respective documentation of their activities; maintains the computerized Oncology Protocol System (ONCPRO) and the computerized tracking system (REX); processes the activation and closure of clinical trials. The office also assists with training of DF/HCC investigators and their staff in regulatory requirements, in the protection of human subjects, and in policies and procedures. The Director is the Executive Officer of the IRB, a voting member of the IRB (and has signatory responsibility for IRB actions). The Director reports to the Senior Vice President for Research at DFCI. The OPRS maintains policies and procedures for their functions. In 2004 and again in 2007, the DF/HCC received full accreditation from the Association for the Accreditation of Human Research Protection Programs (AAHRPP). Revised February 2008 11
  12. 12. D. Clinical Trials Education Office (CTEO): The Clinical Trials Education Office plays a major role in the Human Research Protection Program. The CTEO ensures adequate training for DF/HCC investigators and staff participating in the clinical research process. The CTEO maintains documentation of: staff that have taken the required Human Subjects Protection training; the online Guide to Human Research Activities; NCI Investigator registration; reporting requirements for unexpected and adverse events; forms for research IND submission; special announcements and links to numerous federal and other resources. The CTEO’s mission is to advance clinical research by providing support, education and direction during the clinical trials process and to oversee the training process for clinical research personnel. This office coordinates several educational events each month to train new investigators and research staff and assures that all investigators and research staff obtain human research protection certification. Since March 2003, the CTEO has offered a series of educational opportunities for new and experienced clinical research personnel. Events are offered, on a rotating schedule, at the DFCI and MGH campuses. The sessions are one-two hours in length and are led by speakers internal and external to the DF/HCC. See below for a brief description CTEO sponsored events. The CTEO provides a structure for ongoing training related to clinical research for all DF/HCC institutions. A listserv of staff involved in clinical research is maintained to assist in communicating with our widely dispersed staff. The training program allows continuous refinement of clinical research procedures. The CTEO provides The Guide to Human Research Activities as part of its formal training relating to protocol management for Investigators and study teams involved in clinical trials design and performance. This guide, available on the CTEO website, brings together all details of the clinical trial process for investigators and staff including review and monitoring functions as well as the quality control and protocol management functions. It is updated at least once a year to enhance communication of new policies and procedures. The CTEO provides the following training: 1. Educational Workshops for New Research Staff (series offered quarterly) • Support and Guidance for Clinical Trials-Representatives from the Quality Assurance Office for Clinical Trials (QACT), Research Pharmacy, Research Nursing, Biostatistics Core and Clinical Trials Education Office (CTEO) provide an in-depth review of their roles in the research conducted at DF/HCC. Topics such as protocol development, drug procurement, participant recruitment, in-services, registration, auditing and monitoring activities, and education opportunities are covered in this session. • IRB Process- This workshop focuses on the human subject review process and pertinent federal regulations. The session is designed for those unfamiliar with the IRB review process but is open to veteran research staff looking to refresh their knowledge of the submission and review process. • IRB Forms: A Hands on Approach - This workshop focuses on the completion of DFCI IRB forms. Attendees learn what forms to submit, when to submit them, how to fill them out accurately, and what information should accompany them. The session is open to anyone involved in submitting forms to the DFCI IRB. • Roles and Responsibilities: Protocol Management- This workshop focuses on study coordinator’s responsibilities when it comes to protocol management. Topics covered in this session include navigating a protocol, deviations/violations, pre-study activities, study initiation meetings and participant enrollment. Roles and Responsibilities: Document and Data Management – This workshop focuses on a study coordinator’s responsibilities when it comes to data and document Revised February 2008 12
  13. 13. management. Topics covered in this session include source documents, regulatory binders, research files and case report forms. • Roles and Responsibilities: Adverse Event Reporting – This workshop provides an in-depth review of adverse events including definitions, determinations and reporting requirements for serious adverse events. The session gives real life examples including searching the CTCAE for correct terminology and DF/HCC reporting guidelines. 2. Research Education Seminars (offered monthly)- The Research Education Seminars provide a forum for discussion regarding the issues that investigators and research staff confront. Topics cover ethical issues in clinical research, barriers to day-to-day trial management, and clarifications about how to apply regulations and guidelines to current practice. These seminars are held monthly and are targeted toward experienced investigators and research personnel but anyone involved in clinical research is welcome to attend. 3. Required Human Subject Protection Training- The DFCI IRB has selected the Collaborative IRB Training Initiative (CITI) education program as the required form of training for all personnel participating in research under its auspices. The CITI training consists of two “Core” courses {Biomedical and Social/Behavioral Research (SBR)}. Both courses contain modules, each focusing on those two different aspects of human subject research. The modules, developed by experts in the “IRB Community”, include material that can be read on screen or printed, followed by a brief on-line quiz. Members of the IRB and Scientific Review Committee (SRC) must also complete the program and re-certification is required every three years. E. Research Pharmacy Meeting The DF/HCC research pharmacy representatives from DFCI, BWH, MGH, CH, and BIDMC meet regularly with representatives from the Clinical Trials Operations Committee to review the policies and procedures in place that relate to investigational drugs. Topics include drug procurement and storage, drug accountability logs, dispensing, training, quality control procedures and other investigational drug issues. The research pharmacists report to their Directors of Pharmacies and are represented on the IRB, SRC, CLINPOC and DSMC. F. Data and Safety Monitoring Board (DSMB) A centralized Data Safety Monitoring Board has been created to review all DF/HCC initiated phase III protocols, which do not have an external DSMB established. The QACT manages the administrative functions of the Board. Guidelines set for the DSMB reviewers include: (1) Familiarizing themselves with the research protocol(s) and plans for the data and safety monitoring. (2) Evaluating study summary data to determine protocol progress and whether the trial should continue as originally designed, should be changed, or should be terminated based on these data. (3) Reviewing reports of related studies to determine whether new information means the monitored study needs to be changed or terminated. (4) Review in major proposed modifications to the study prior to their implementation (e.g. termination, dropping an arm based on toxicity results or other reported trial outcomes, increasing target sample size). (5) Following each DSMB meeting, provide the study team with written information concerning findings for the trial as a whole related to cumulative toxicities observed and any relevant recommendations related to continuing, Revised February 2008 13
  14. 14. changing or terminating the trial. The DSMB provides a summary of the board findings to the IRB, CLINPOC and the principal investigator. The DSMB membership includes the voting membership of the board who is appointed by the Senior Vice President for Research. The DSMB chair is selected from the voting members. Voting members include physicians, statisticians, other scientists, based on their experience, reputation for objectivity, absence of conflicts of interest, and knowledge of clinical trials methodology. The following members have been selected for the DF/HCC DSMB. Chair, Medical Oncologist (External, outside DF/HCC) Medical Oncologist (External, outside DF/HCC) Medical Oncologist (DF/HCC) Other Scientist (radiologist or surgeon –within DF/HCC) Statistician (External, outside DF/HCC) Ad Hoc membership (if special expertise is needed) The Chair of the Department of Biostatistics and Computational Biology will serve ex officio as a non- voting member of the DSMB. With the prospective permission of the DSMB Chair and the Chair of CLINPOC, guests may attend a DSMB meeting to observe for educational purposes. The invited guest will be required to sign a confidentiality agreement prior to the meeting. If the invited guest is affiliated with any of the trials under review, he/she will be asked to leave for the closed session review of that trial. Voting members may be from within or outside the institution, but a majority should not be affiliated with the institution. Voting members should not be directly involved with the conceptual design or analysis of the trial. The meeting is held at least semi-annually depending on the nature and volume of the trials being monitored. Each meeting will have 3 parts: (1) An open session in which members of the trial team, including the statistician, may be present, at the request of the DSMB, to review the conduct of the trial and to answer questions from members of the DSMB. The focus of this open session may be on accrual, protocol compliance, and general toxicity issues. Outcome results must not be discussed during this session. (2) A Closed session of the DSMB should be held to allow discussion of the general conduct of the trial and all outcome results, including toxicities, and adverse events, develop recommendations and take necessary votes. 3) A summary executive session to summarize and evaluate the overall meeting, and to plan the next meeting. The meeting may occur by conference call if necessary. Both the DSMB minutes and PI reports will usually not include confidential outcome data. For studies that remain blinded, outcome data will not be made available to individuals outside of the DSMB. Any special release of this data should be approved by the DSMB. In instances where the DSMB recommends changes to the design of a study (including early stopping of enrollment because of the results of an interim analysis or changes in one or more of the treatments), the DSMB will provide in writing to protocol PI a rationale for these recommendations. Outcome data for protocols still enrolling patients are considered confidential and are not to be discussed outside the DSMB meetings. Outcome data may be released to the study team for manuscript preparation or planning of future studies only after review and approval by the DSMB. No communications of the deliberations (either written or oral) or recommendations of the DSMB will be made outside the DSMB except as provided for in this policy. Revised February 2008 14
  15. 15. The study team should implement recommendations from the DSMB expeditiously. When requested by the DSMB, the protocol PI will respond in writing to the DSMB and DFCI IRB of the actions taken regarding the recommendations and the reasons for that decision. The DFCI IRB will adjudicate any disagreements between the DSMB and the protocol PI. Trials being monitored by the DF/HCC DSMB will remain under the DF/HCC DSMB review until either the last enrollment occurs, or until the DSMB feels there are no patient safety concerns that require further monitoring. The DSMB will determine the length of continued review on a study-by-study basis. The DF/HCC expects that the DSMB will act in a way that is consistent with the intent of the design of a protocol and in the best interests of the study participants. In some instances, the DSMB may recommend changes to the design of a protocol, the timing of data collection, or the details of an analysis because either the assumptions made in the original design are not true, or because of data external to the study. The deliberations of the DSMB should not be influenced by special interests of either the study team or the protocol sponsor. Each member of the DSMB must sign a confidentiality agreement. DSMB members will be expected to follow the Harvard Medical School guidelines for disclosing conflicts of interest and will sign a statement agreeing to that policy at every meeting. G. Data and Safety Monitoring Committee (DSMC) The committee was initiated in October of 2002 and is responsible for reviewing Pilot, Phase I or II high risk protocols and protocols requiring very close monitoring such as gene transfer protocols. High risk protocols include: • DF/HCC PI-initiated Pilot, Phase I or I/II trials which involve the use of a drug for the first time in adults and/or children • DF/HCC PI-initiated or led, multi-center phase I/II trials • Vaccine trials using live or attenuated viruses • Gene transfer protocols • Unusually complex or intensive protocols • Studies involving an IND held by a DF/HCC PI This committee consists of internal DF/HCC faculty and staff to allow the meetings to occur quarterly and/or more regularly if required. The QACT provides administrative support for the DSMC. The PI must complete a form that describes toxicities and study progress for each protocol that has been identified as high risk. Reviewers are assigned to each protocol and they present the review at the meeting. Follow- up occurs as needed and the protocol is continuously monitored until completion. Meeting summary reports are provided to the IRB and CLINPOC after each meeting. H. Institutional Review Board (IRB) The purpose of the IRB and its review is to protect the participant, the researcher and the DF/HCC- by ensuring that ethical and moral principles are adhered to in research. This is done through careful review of the protocol document, the accompanying informed consent document and supplemental documents, such as questionnaires, diaries and recruitment materials. The members of the IRB include medical, Revised February 2008 15
  16. 16. nursing, pharmacy, legal representatives, a medical ethicist, and lay members from the community and across DF/HCC who have special interest in helping the Institute maintain a high standard of research. The DFCI IRB is the IRB of record for DF/HCC research and the sole IRB to review all adult and pediatric oncology research protocols, including all oncology related social and behavioral research and non-malignant hematology clinical trials. The IRB adheres to the regulations set forth in the federal regulations as determined by the Food and Drug Administration, the Department of Health and Human Services, and the Massachusetts Department of Public Health. An IRB panel membership has a minimum of five members and is composed of at least two (2) licensed physicians, and at least one (1) non-scientist and at least one (1) member who is not otherwise affiliated with the DFCI. Other members include representatives from the medical departments, nursing, social services, pharmacy and statistical representatives. There may also be legal, clerical and medical ethics representation. Physicians who serve on the IRB hold academic appointments and represent the major disciplines in Oncology at the DF/HCC hospitals. There are currently four IRB panels registered with the Office for Human Research Protections in Washington D.C. These IRBs consist of representation from all DF/HCC hospitals and meet at least eight times per month. The Chairperson holds a terminal degree in medicine and is a voting member. The Director of the Office for the Protection of Research Subjects (OPRS) serves as the Executive Officer of the IRB and is a voting member. The Chairperson and Executive Officer are responsible for the interpretation, enforcement, and implementation of regulations as they pertain to human subject research. When necessary, the Chairperson, at his or her discretion, supplements the expertise of the IRB by appointing Ad Hoc members for participation in discussions at designated meetings. These Ad Hoc Members do not vote. The committee membership is appointed through the Senior IRB Chair with the concurrence of the President of the DFCI. Members are appointed on a 3-year basis subject to reappointment at the discretion of the Chair and with the agreement of the member. The committee is notified of the Conflict of Interest Policy at every meeting on each agenda. Members are required to leave the meeting if they have a conflict of interest with the protocol being reviewed. I. Scientific Review Committee (SRC) The DF/HCC is an NCI-designated comprehensive cancer center. As such, the DF/HCC is required to provide scientific review of its clinical trials and other “more than minimal risk” studies. The SRC is responsible for reviewing the study rationale, study design, duplication of studies already underway, adequacy of the biostatistical input as well as the feasibility for completion of the study within a reasonable time frame. The outcomes of these reviews are forwarded to the IRB for consideration during their deliberations. PIs respond to the comments made by the SRC before the study is sent to the IRB. The SRC membership is appointed through the SRC Chairperson with the concurrence of the Senior Vice President for Research. Physicians who serve on the SRC hold academic appointments at the level of Assistant Professor or above, and represent the major disciplines and Disease Programs of the DF/HCC in Adult Oncology. The committee is comprised of the Scientific Chair, an Executive Officer and Physicians, as well as representatives from QACT, Biostatistics, Radiation Safety, Bio-safety, Social Services, Pharmacy, Nursing, and other departments that are involved in clinical research such as Surgery. The Chair can, at his/her discretion, approve the changes (an expedited SRC review) or have them reviewed and voted on by the full committee. The Director of OPRS serves as the Executive Officer of the SRC but does not vote. The SRC reviews all oncology treatment trials that are considered to be greater than minimal-risk trials involving adult subjects. The SRC reviews the novelty and importance of the therapeutic questions, the Revised February 2008 16
  17. 17. feasibility of the research plan, the capability of the research team to conduct the trial in a timely fashion, and whether the protocol is competing with other protocols already underway. The committee is notified of the conflict of interest policy (stated above) on every agenda, and members absent themselves if there is a conflict of interest with the protocol being reviewed. If a conflict of interest exists between a reviewer and his/her assigned project, it is the reviewer’s responsibility to notify the OPRS upon receipt of the meeting packet. Ad hoc reviewers may be assigned if deemed necessary by the SRC Chairperson. J. Pediatric Scientific Review Committee (PSRC) The PSRC reviews all risk studies involving pediatric patients, and ensures that the protocol is of appropriate scientific and therapeutic merit and is in accordance with the scientific plan of the Institute. All investigators from the Division of Hematology/Oncology at Children’s Hospital or the Department of Pediatric Oncology at the Dana-Farber Cancer Institute must submit protocol to the PSRC for review and approval. The committee chairperson appoints the membership. Membership includes a representative from the major disciplines and includes physicians, nurses, pharmacists, biostatisticians, Children’s Oncology Group (COG) clinical research coordinators, and the Director of OPRS. The committee may supplement its membership at any time to ensure proper scientific review. The PSRC Chair may call upon the support of ad hoc reviewers for assistance in areas of expertise, balance of review, unavailability of other appropriate reviewers, etc. K. Connell & O’Reilly Families Cell Manipulation Core Facility (CMCF) and DFCI Clinical Research Laboratory (CRL) Good Laboratory Practices (GLP) and Good Manufacturing Practices (GMP) are monitored through the CMCF and CRL specific quality assurance standard operating procedures. These SOPs are maintained by the Quality Assurance Managers in each department. III. ASSURING COMPLIANCE WITH REQUIREMENTS FOR REPORTING ADVERSE EVENTS: All protocols are required to have a protocol section describing the adverse event reporting. The Overall or Site Principal Investigator (PI) must report all significant adverse events (AE) for drugs, biologics or devices to the DFCI Institutional Review Board (IRB), to the protocol sponsor (including the NCI Program Director) and, when applicable, to national chairs of multi-center/group studies, Institutional Bio-safety Committees, FDA and NIH/OBA (Office of Biotechnology Activities). The treating physician is responsible ONLY for notifying the Overall or Site PI of the incident. When an AE occurs involving a participant being treated or followed by a physician outside DF/HCC and there is a time requirement involved, all reporting should take place within the 10 working days based on a start date of the time of notification to the overall PI. Copies of ALL reports should be submitted to the Office for the Protection of Research Subjects (OPRS). They will then be forwarded to the DFCI IRB for review. For studies that require a report to be filed with other agencies (study sponsor, FDA, NIH/OBA, Institutional Biosafety Committees, etc.) submission to the OPRS DOES NOT substitute for a report directly to these agencies from the overall Principal Investigator. Revised February 2008 17
  18. 18. A. DFCI IRB Requirements and Reporting: Unanticipated risks are sometimes discovered during the course of research. Information that may impact the risk/benefit ratio should be promptly reported to, and reviewed by, the IRB to ensure adequate protection of the welfare of the subjects. Based upon such information, the IRB may need to reconsider its approval of the study, require modifications to the study, or revise the continuing review timetable. The IRB is responsible for ensuring that reports of unanticipated problems involving risks to human subjects or others are reported to the appropriate government office {21 CFR 56-108 (b) (1) and 45 CRF 46}. Serious Adverse Events (SAE) are be submitted on the DFCI IRB SAE form. One of these forms must be submitted in addition to any sponsor/company or other forms except where AdEERS online reporting is used. However, if the report is done on a sponsor/company or other form, only the following fields of the IRB SAE form have to be completed: protocol number, protocol title, PI name, relation of the event to any part of the protocol treatment, severity of the event, and protocol or consent form changes. In cases where an SAE occurs involving a patient being treated or followed by a physician outside DF/HCC and there is a time requirement involved, all reporting should take place within the time specified based on a start date of the time of notification to the overall PI. It is required that the PI or designee keeps a copy of all submitted SAE reports in the study files. B. IND Safety Reports: IND Safety Reports are adverse event reports submitted by sponsors to local investigators detailing any adverse events that occur at other sites. These reports must be submitted to the DFCI IRB, along with the DFCI IRB IND Safety Reporting Form. IND Safety Report forms usually reflect the evaluation of the event by the investigator at whose site the adverse event occurred and the sponsor’s evaluation. If the investigator at DF/HCC does not agree with the IND Safety Report evaluation of the event, the DF/HCC investigator should make a note on the DF/HCC IND Safety Reporting Form and complete the form according to his/her assessment of the event. The other reporting requirements are: (1) If PI-Initiated/Sponsor holds IND then the sponsor, as the holder of the IND/IDE, is responsible for forwarding all reported adverse events to the FDA. The DF/HCC PI, in addition to the DFCI IRB form, may also be required to complete a form supplied by the sponsor. The DFCI IRB’s reporting requirements may differ from the sponsor’s. DF/HCC investigators must comply with both. (2) Industry Sponsored (Investigational) Same as (1). (3) Industry Sponsored (Commercial) The FDA’s MedWatch Online form, #3500, may be used to voluntarily report serious adverse events, potential and actual medical product errors, and product quality problems associated with the use of FDA-regulated drugs, biologics, devices, and dietary supplements. The sponsor of the trial, however, may have its own form. C. Adverse Event Reporting Guidelines for DF/HCC (what or when to report) If an Adverse Event occurs while a subject is on a trial the following reporting guidelines are used: Revised February 2008 18
  19. 19. • Grade 2 (moderate) and Grade 3 (serious) Events – Only events that are Unexpected and Possibly, Probably or Definitely Related/Associated with the Intervention. • ALL Grade 4 (life threatening) Events – Unless expected AND specifically listed in protocol as not requiring reporting. • ALL Grade 5 (Fatal) Events – When subject is enrolled and actively participating in the trial OR when event occurs within 30 days of the last study intervention. A Full written SAE report must be submitted to OPRS as soon as possible, but no later than 10 working days from notification of the event. SAE reports should be submitted via OPRS Submit except for AdEERs reports, which are submitted via email to the OPRS ( If subject is in Long-Term Follow Up, death is reported at continuing review. The protocol is to be referred to for additional reporting requirements (to sponsor, FDA, etc) Human Gene Transfer (Per OBA Guidelines, Appendix M-I-C-4 ) The following must be reported: (1) any SAE that is both unexpected and associated with the use of the gene transfer product (2) any new finding from animal testing that presents a significant risk for human research. Reports must be sent: (1) Within 15 days if unexpected and associated; (2) Within 7 days if fatal or life- threatening, unexpected and associated; (3) Follow-ups for previously reported events must be sent no later than 15 days of receipt by the investigator/sponsor; (4) Any event that occurs after the end of a trial and is associated with the use of the gene transfer product must be reported within 15 days of the determination; and (5) Any finding from tests in laboratory animals that suggests a significant risk for human research participants including reports of mutagenicity, teratogenicity, or carcinogenicity must be reported as soon as possible, but no later than 15 days after the sponsor’s initial receipt of the information. Submit the appropriate IRB form to the following: Institutional Biosafety Officer, sponsor, if applicable (may have own reporting form) FDA (if Serious and Unexpected, or death) NIH/OBA ** All subject/patient identifiers are to be removed prior to submission to the above. The PI is responsible for reporting all applicable adverse events to NIH/OBA. Under the NIH Guidelines for Research Involving Recombinant DNA Molecules, a PI may delegate the reporting responsibilities set forth in Appendix M-I- C to another party (i.e., the sponsor), with written notification of the delegation to OBA. The protocol document should outline the reporting policy. D. Definitions: Adverse Event: Any unfavorable and unintended sign (including an abnormal laboratory finding), symptom or disease temporarily 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 unrelated, unlikely, possible, probable or definite). (NIH Guidelines, January 2001) Serious Adverse Event: Any adverse drug experience occurring at any dose that results in any of the following outcomes: Death, a life-threatening adverse drug experience, inpatient hospitalization or prolongation of existing hospitalization, and persistent or significant disability/incapacity, or a congenital anomaly/birth defect. Important medical events that may not result in death, be life-threatening or require Revised February 2008 19
  20. 20. hospitalization may be considered a serious adverse drug experience when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition (21CFR312.32a) Life-threatening Adverse Event: Any adverse drug experience that places the patient or subject, in the view of the investigator, at immediate risk of death from the reaction as it occurred, i.e., it does not include a reaction that had it occurred in a more severe form, might have caused death (21CFR312.32a) Unexpected Adverse Event (FDA definition): Any adverse drug experience, the specificity or severity of which is not consistent with the current investigator brochure; or, if an investigator brochure is not required or available, the specificity or severity of which is not consistent with the risk information described in the general investigational plan or elsewhere in the current application, as amended. “Unexpected” as used in this definition, refers to an adverse drug experience that has not been previously observed (e.g., included in the investigator brochure) rather than from the perspective of such experience not being anticipated from the pharmacological properties of the pharmaceutical product (21CFR312.32a) Unexpected Adverse Event (NCI definition): Any adverse event which is not listed in the NCI Agent Specific Expected Adverse Event List. This list is updated electronically in real time. 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 investigational agent(s). Probable: The adverse event is likely related to the investigational agent(s). Possible: The adverse event may be related to the investigational agent(s). Unlikely: The adverse event is doubtfully related to the investigational agent(s). Unrelated: The adverse event is clearly NOT related to the investigational agent(s). IV. PROCESS FOR ASSURING THAT ANY ACTION RESULTING IN TEMPORARY OR PERMANENT SUSPENSION OF AN NCI-FUNDED CLINICAL TRIAL IS REPORTED TO THE NCI GRANT PROGRAM DIRECTOR RESPONSIBLE FOR THE GRANT All temporary or permanent closures of NCI-sponsored clinical trials (non cooperative group) as specified below will be reported by the OPRS to the appropriate NCI Grant Program Director. Protocols that are closed due to non-compliance or safety concerns by the IRB or DF/HCC will be reported immediately to the NCI Grant Program Director. V. PROCESS FOR ASSURING DATA ACCURACY AND PROTOCOL COMPLIANCE As described above, there are extensive procedures in place to assure compliance and data accuracy for DF/HCC protocols. These include: eligibility checking; centralized protocol participant registration; the internal auditing program; the quality assurance process for computerizing clinical trial data for PI initiated and NCI-sponsored clinical trials; DSMPs in each protocol; DSMB and DSMC for those protocols that require them; and extensive training of Physicians, study coordinators and research nurses. The data from DF/HCC-initiated trials or NCI-sponsored trials that do not have data management by the sponsor are computerized in the QACT. This involves a formal process of case report forms design, forms testing, computerization of data, data querying for missing or ambiguous data, and data cleaning. Reports are generated for the study team as requested and the data are analyzed by the Cancer Center biostatisticians. This process is overseen by the QA Officer for Clinical Trials. Problems with obtaining Revised February 2008 4 20
  21. 21. data or data quality are referred either to the auditing program or to CLINPOC, depending on the circumstances. Problems with suspected misconduct are reported to the Vice President for Research. Revised February 2008 21
  22. 22. APPROVED CLINICAL PROTOCOL Revised February 2008 Clinical Trials Support Protocol Activation and Management Appendix I DF/HCC Clinical Trials System CLINPOC CLINICAL TRIALS SUPPORT STRUCTURES I. Single Point Contracting 2. Common Protocol Management System 3. Common Patient Registration System 4. Common Auditing System 5. Integrated Biostatistics 6. Integrated Research Pharmacy Support INSTITUTIONAL REVIEW BOARD SCIENTIFIC REVIEW COMMITTEE DISEASE PROGRAM 1. Review Scientific Validity 2. Determine Clinical Importance and Priority 3. Disease Program Sign Off New Clinical Protocol Concept SINGLE IRB 1. Adult SRC and/or 2. Pediatric Oncology SRC 1. 12 Adult DISEASE PROGRAMS and/or 2. Pediatric DISEASE PROGRAMS INDIVIDUAL OR GROUPS OF INVESTIGATORS 22
  23. 23. Revised February 2008 Clinical Trials Process Note: Detailed process steps may vary according to specific study and funding source • Concept review by appropriate Disease Programs for scientific validity, clinical importance and priority • Initial review by OPRS • SRC/ Early reviewers and Biostat • IRB • Determine in-service requirements (radiation safety services, pharmacy services, nursing services) • Design data forms • Have negotiated contract (if w/ industry) • Eligibility checking and enrollment • Forms Completion • Receive data • Program interim reports and complete missing data • Data is transferred to analysis site (e.g., DF/PCC Biostat, industry sponsor) • Design study • Write protocol • Administer treatment to patients according to research protocol • Prepare scientific paper discussing the experiment, methodology, results and implications • Publicize Protocol activation PRE-APPROVAL APPROVAL PERFORMANCE REPORTANALYSIS Single point contract negotiation w/ industry (if study is w/ industry) Report Protocol Approval Patient Enrollment Treatment Forms Completion & Data Collection Data Analysis Protocol Design & Development Protocol Review Data Clean-Up Quality Assurance, Quality Control, and Audit Data Management • Review data • Batch data and enter • Protocol compliance Appendix II Dana-Farber/Harvard Cancer Center 23
  24. 24. Revised February 2008 STUDY TEAM DATA ANALYST - Early protocol review - Data Collection Forms design - Set up and maintain computerized database - Creates and distributes data query reports - Prepares data for statistical analysis BIOSTATISTICIAN - Early protocol review - Prepares statistical section - Interim analysis - Data Collection Forms design SITE PRINCIPAL INVESTIGATOR -Responsible for conduct of trial at their institution, including data management/ collection -Collaborates with Overall P.I. on conduct of trial OVERALL PRINCIPAL INVESTIGATOR - Protocol Development - Overall responsibility for conduct of the study - Data Collection Forms design - Oversees Data Manager CLINICAL RESEARCH COORDINATOR (CRC)/ASSOCIATE (CRA) /RESEARCH NURSE - Data Collection Forms design - Confirms eligibility and signed consent - Registers patients with the QACT - Ensures protocol compliance for required data - Coordinates general management of study Appendix III 25