The Guide to Human Research Activities

Transcription

1 The Guide to Human Research Activities 1 The Guide to Human Research Activities Dana-Farber/Harvard Cancer Center Contributors: Office for Human Research Studies Office of Data Quality Clinical Trials Research Informatics Office Research Pharmacy Research Nursing Biostatistics Core Biosafety Officers Office of Faculty Activities

2 The Guide to Human Research Activities 2 CONTENTS I. PREFACE AND ACKNOWLEDGMENTS II. DESCRIPTION OF INSTITUTIONAL RELATIONSHIPS III. INTRODUCTION IV. SECTIONS 1: Clinical Trials and Sponsorship 2: Offices and Staffing Central to the Clinical Trials Process 2.1 Office for Human Research Studies (OHRS) 2.2 The Office of Data Quality (ODQ) 2.3 The Clinical Trials Research Informatics Office (CTRIO) 2.4 Dana-Farber Cancer Institute (DFCI) Clinical Trials Office (CTO) 2.5 Massachusetts General Hospital (MGH) Cancer Center Protocol Office (CCPO) 2.6 Beth Israel Deaconess Medical Center (BIDMC) Cancer Clinical Trials Office (CCTO) 2.7 Clinical Investigations Leadership Committee (CLC) 2.8 Clinical Trials Operations Committee (CLINOPS) 2.9 Institutional Review Board (IRB) 2.10 Scientific Review Committee (SRC) and Scientific Progress Review 3: The Study Team 3.1 Overall Principal Investigator (Overall PI) 3.2 Site Principal Investigator (Site PI) 3.3 Collaborating Investigators (Co-investigators) 3.4 Biostatistician 3.5 Research Nurse 3.6 Study Coordinator 3.7 ODQ Data Analyst 4: Investigator and Study Staff Complaints and Suggestions 5: DF/HCC Standard Operating Procedures (SOPs) 6: Research Listserv and DF/HCC Membership 6.1 Subscribe to the Research Listserv 6.2 DF/HCC Membership and DF/HCC Website Access 7: Required Human Subjects Training 7.1 The CITI Program 7.2 Courses

3 The Guide to Human Research Activities Certification 7.4 DF/HCC Training List 7.5 Continuing Human Subjects Protection Education 8: Federal Guidelines for Research Involving Human Subjects 9: Degree of Risk 9.1 Minimal Risk 9.2 Greater than Minimal Risk 10: Research Methods for Drug Studies 10.1 The Drug Development Process 10.2 Types of Trials Pre-Clinical Phase I Phase II Phase III Phase IV Multi-Modality Trials 11: Expanded Access to Investigational Treatment 11.1 Emergency Use 11.2 Treatment IND (Single Patient IND) 12: Tissue/Data Collection and Record Review 12.1 Banking Specimens and/or Data for Future Research 12.2 Access to Banked Tissue/Data by Other Investigators 12.3 Research Involving Previously Banked Tissue 12.4 Research Involving Record Reviews 13: Medical Devices 13.1 Definition 13.2 Ordering 13.3 Storage 13.4 Authorization 13.5 Dispensing 13.6 Destroying 14: Behavioral/Social Science Research 15: Vulnerable Populations 15.1 Inclusion of Children as Participants in Research 15.2 Pregnant Women and Fetuses in Research 15.3 Cognitively Impaired Persons Involved in Clinical research 15.4 Research Involving Prisoners

4 The Guide to Human Research Activities 4 16: Recruiting Trials Participants 16.1 Private Medical Information 16.2 Referring Physicians 16.3 Advertisements 16.4 Recruitment Letters 16.5 Scripts 16.6 Unacceptable Language and Suggested Alternatives 17: Pre-screening Potential Trial Participants 17.1 Appropriate Information to Gather 17.2 Pre-screening Procedures 18: Protocol Design 18.1 The Protocol Document 18.2 Protocol Sections 19: Informed Consent 19.1 Informed Consent Document 19.2 Standardized Consent Form Template 19.3 Incentives and Remuneration for Study Subject Participation 19.4 Assent and Children in Research 19.5 IRB Waiver of Informed Consent 19.6 IRB Waiver of Documentation of Informed Consent 19.7 Guidelines for Obtaining Consent 19.8 DFCI IRB Policy and Guidance on the Consent Process 20: Protocol Submission, Review and Activation 20.1 The Review Process 20.2 Submitting a Trial for Review 20.3 Basic Elements of an IRB Submission 20.4 Other Documents that May Be Required 20.5 The Review Committees 20.6 Description of Protocol Reviewers 20.7 Review and Approval by Other DF/HCC Departments/Committees 20.8 Notification of Board Actions 20.9 Review Outcomes Response to Committee Requests Claim of Exemption New Submission Flow Chart Protocol Activation and Distribution 21: Continuing Review

5 The Guide to Human Research Activities 5 22: Changes to Previously Approved Research (Amendments) 22.1 Overview 22.2 Types of Amendment Submissions 22.3 Amendment Submission Requirements 23: Reports of Non-Compliance (Deviations, Violations, Exceptions and Other Events) 23.1 Overview 23.2 Major Deviations / Violations / Exceptions 23.3 Minor Deviations / Violations 23.4 Other Events 24: Unanticipated Problems Involving Risks to Participants or Others 25: Adverse Event (AE) Reporting Policy 25.1 Definitions 25.2 Adverse Event Grading System 25.3 Attribution 25.4 DFCI IRB Requirements 25.5 AE Reporting Form 25.7 CTEP-AERS 25.8 AE Follow-up Reports 25.9 Gene Transfer Reporting Requirements PI-initiated/IND Holder Reporting Requirements PI-initiated/Sponsor Holds IND Reporting Requirements Industry-sponsored (Investigational) Reporting Requirements Industry-sponsored (Commercial) Reporting Requirements 26: Privacy and Confidentiality 26.1 Health Insurance Portability and Accountability Act of 1996 (HIPAA) 26.2 What Constitutes PHI? 26.3 Minimum Necessary Standard for Research Activities 26.4 De-identified Information for HIPAA Privacy Rule 26.5 The Limited Data Set Option 26.6 Data Use Agreement Requirements 26.7 Accounting for Disclosures 26.8 Research on Deceased Persons 26.9 Waiver of Authorization for Research 27: Department of Biostatistical Science 27.1 Biostatistical Support for the Protocol Development Process 27.2 Biostatistical Support for Forms Development 27.3 Biostatistical Support for Data Collection and Storage 27.4 Biostatistical Support during Protocol Activation 27.5 Role of Biostatistics in Monitoring Active Trials

6 The Guide to Human Research Activities Biostatistics Involvement in Protocol Addenda 27.7 Analyses/Reports on DF/HCC Trials 28: Office of Data Quality (ODQ) 28.1 Introduction and Purpose 28.2 Mission 28.3 Functions of the ODQ 28.4 Participant Enrollment in Clinical Trials 28.5 Randomization Process 28.6 Phase I Dose-escalation Trials 28.7 Single Patient IND 28.8 Non-protocol Standard Treatment Registration 28.9 DF/PCC Network Affiliate Registration Industry-led and Cooperative-group Registration Non-patient Volunteer Registration Electronic Confirmation of Registration After-hours Registration Removing a Participant from a Research Study Protocol Closure Notification Protocol Completion/Termination Notification Reports Available from the Clinical Trials Research Informatics Office Protocol Accrual Monitoring Case Report Form (CRF) Design Documentation and Storage of Data Accrual-monitoring Program Internal Auditing DF/HCC Data and Safety Monitoring Board (DSMB) DF/HCC Data and Safety Monitoring Committee (DSMC) 29: Education 29.1 Programs for Clinical Investigators Study Team Members 29.2 Programs for Study Team Members 29.3 Professional Certification of Study Team Members 29.4 elearning Center 29.5 In-Services 30: NCI Investigator Registration and Renewal 31: Protocol Registration Requirements 31.1 ClinicalTrials.gov 31.2 Clinical Trials Reporting Program (CTRP) 32: Principal Investigators (PIs) 32.1 General Responsibilities of the PI

7 The Guide to Human Research Activities Financial Disclosure by Clinical Investigators 32.3 Conflict of Interest Policy 33: Study Coordinators 33.1 Roles and Responsibilities 33.2 Protocol Management 33.3 Data Management 33.4 Drug Accountability 33.5 Regulatory Submissions 33.6 The Regulatory Binder 33.7 Research Sampling 33.8 Monitoring and Audit Preparation 33.9 Checklist for Monitoring and Auditing Visits 34: Investigator-held INDs 34.1 IND Overview 34.2 General Principles of the IND Submission 34.3 IND Content and Format 34.4 Submission of the IND Application to the FDA 34.5 IND Application Approval Process 34.6 IND Post-Approval 34.7 IND Protocol Amendments 34.8 IND Safety Reports for Investigator-held INDs 34.9 IND Annual Reports Final Study Reports Withdrawal of an IND Application General Responsibilities of the Investigator-Sponsor Selecting Participating Investigators and Monitors Informing Participating Investigators of New Observations Reviewing Ongoing Investigations Record Keeping and Record Retention Inspection of Records and Reports Disposition of Unused Investigational Drug General Responsibilities of Participating Investigators Control of the Investigational Drug Participating Investigator Record Keeping and Record Retention Participating Investigator Reports 35: Conducting PI-initiated Multi-center Trials at DF/HCC 35.1 Purpose and Function of a Lead Site 35.2 Overall PI Responsibilities 35.3 Lead Site Responsibilities 35.4 Participating Site PI Responsibilities 35.5 Regulatory Binder

8 The Guide to Human Research Activities Staff Training 35.7 Central Participant Registration 35.8 Adverse Event Reporting 35.9 Data Collection Quality Assurance Site Communication Drug Ordering Inter-institutional Agreement/Contract Multi-center Coordinating Committee 36: Gene Transfer Research (Recombinant DNA) 37: Evaluation of Outreach Activities and Catchment Area V. Appendix R.1 Code of Federal Regulations R.2 Good Clinical Practice Guidelines R.3 Medical Terminology, Dictionaries and Other Resources R.4 Ethics References R.5 External Web Sites R.6 DF/HCC Web Sites R.7 DF/HCC Participating Institutions R.8 Regulatory Documents for Sponsors R.9 DF/HCC SOPS for Human Subject Research R.10 Office for Human Research Studies Information Sheets R. 11 Additional Regulations and Standards

9 The Guide to Human Research Activities 9 I. PREFACE AND ACKNOWLEDGMENTS In June 1996, the Dana-Farber Cancer Institute (DFCI) formalized its collaboration with Brigham and Women s Hospital (BWH) and the Massachusetts General Hospital (MGH) to establish the Dana-Farber/Partners Cancer Care (DF/PCC) system. This venture merged the three adult cancer care practices and provided the opportunity and impetus to form new collaborations in clinical research activities. In 1999, Dana-Farber and its affiliates formed the Dana-Farber/Harvard Cancer Center (DF/HCC), a collaboration designed to bring seven Harvard-affiliated institutions together: Beth Israel Deaconess Medical Center (BIDMC), Brigham and Women s Hospital (BWH),Boston Children s Hospital (BCH), Dana-Farber Cancer Institute (DFCI), Massachusetts General Hospital (MGH), Harvard Medical School, and Harvard School of Public Health. This effort continues to be supported by the renewals of Dana-Farber s Comprehensive Cancer Center support grant from the National Cancer Institute (NCI) since October All adult oncology services, medicine, radiotherapy, and surgery are coordinated under a common management system. As a result of this collaboration, DF/HCC is the largest cancer care provider in New England and is one of the largest single contributors to NCI-sponsored clinical research in the United States. The Guide to Human Research Activities outlines the current practices and procedures involved in the human research process at the DF/HCC. The guide is directed toward staff who are or who will be involved with conducting human research trials: investigators, research nurses, project managers, study coordinators (SCs), and data managers, among other individuals involved in the research process. New fellows and data management staff may find the material particularly useful as they become acquainted with their roles. The DF/HCC complies with all Federal regulations governing the conduct of research involving human subjects. For human subject review and approval purposes, the Office for Human Research Studies (OHRS) has independent authority and the ability to access and communicate with the most senior officials including the Chief Executive Officer (CEO), as appropriate. Questions regarding the conduct of DF/HCC research may be forwarded to representatives in the Office for Human Research Studies (OHRS) and the Office of Data Quality (ODQ) All DF/HCC institutions will follow the processes outlined in this manual for all oncology clinical trials involving DF/HCC subjects. The text contained in this manual is revised as policies and procedures change. Contributors: Office for Human Research Studies (OHRS) Office of Data QualityResearch Pharmacy Research Nursing Biostatistics Core Biosafety Officers Office of Faculty Activities

10 The Guide to Human Research Activities 10 II. DESCRIPTION OF INSTITUTIONAL RELATIONSHIPS The following is meant to clarify the terms and relationships between the institutions covered by the processes outlined in this manual. Dana-Farber/Harvard Cancer Center (DF/HCC) Dana-Farber/Harvard Cancer Center (DF/HCC) is the largest National Cancer Institute (NCI) comprehensive cancer center in the world, bringing together the cancer research efforts of the following seven Harvard affiliated member institutions: Beth-Israel Deaconess Medical Center (BIDMC) Boston Children s Hospital (BCH) Dana-Farber Cancer Institute (DFCI) Brigham and Women s Hospital (BWH) Harvard Medical School (HMS) Harvard School of Public Health (HSPH) Massachusetts General Hospital (MGH) Satellites: The satellite sites are licensed under each noted main institution (BIDMC, DFCI or MGH). They abide by DF/HCC policies and procedures for the conduct of research. The satellite sites include: Beth Israel Deaconess Medical Center Needham Dana-Farber/Brigham and Women s Cancer Center at Milford Dana-Farber/Brigham and Women s Cancer Center at Londonderry Dana-Farber/Brigham and Women s Cancer Center at South Shore Dana-Farber Cancer Institute at Steward St. Elizabeth s Medical Center Massachusetts General Hospital Cancer Center at Emerson-Bethke Massachusetts General at North Shore Cancer Center Network Affiliates: The Network Affiliates is a program that extends to affiliated community hospitals a select range of Phase II and III DF/HCC clinical trials. The DFCI clinical trials network office manages and coordinates the communi-

11 The Guide to Human Research Activities 11 cation, training, site assessments, IRB and other regulatory approvals, study activations and auditing. Network Affiliates Sites Include: Cape Cod Healthcare (CCHC) - Hyannis, MA and Falmouth, MA Lowell-General Hospital (LGH) - Lowell, MA New Hampshire Oncology-Hematology, PA (NHOH) - Hooksett, NH Newton Wellesley Hospital (NWH) Lawrence + Memorial through Dana-Farber Community Cancer Care

12 The Guide to Human Research Activities 12 INTRODUCTION The Dana-Farber/Harvard Cancer Center (DF/HCC) is one of the country s federally designated comprehensive cancer centers. As such, DF/HCC is responsible for all aspects of cancer care ranging from basic scientific research and research subject care (both pediatric and adult) to the training and education of future cancer specialists. DF/HCC also provides outreach programs to help educate laypersons and affiliated community hospitals about up-to-date cancer treatments. At the core of the DF/HCC s responsibilities is the conduct of basic research. Because there is currently no known cure for many cancers, treatment relies on the advances of research. Many treatments at the DF/HCC are presented in the form of research protocols, otherwise known as clinical trials. Pertinent information also is obtained through non-clinical trials such as research involving specimens or data, community-based research or research involving the use of a questionnaire. This type of research also is conducted at DF/HCC. This guide outlines the course of the clinical trial process from beginning to end and identifies the procedures for the various steps in the process. It will also address non-clinical trial research that makes up a large portion of the work done by investigators in the DF/HCC. The guide also describes what investigators need to know about their responsibilities, including subject registration policies, adverse event reporting, subject confidentiality, and informed consent. Ultimately, the goal of this guide is to identify standards to ensure consistent and uniform research practices.

13 The Guide to Human Research Activities 13 Section 1 Clinical Trials and Sponsorship The DF/HCC trials can be categorized by the Study Source (funding category) defined by the NCI in the Cancer Center Support Grant (CCSG): National trials: These are trials supported by the NCI National Clinical Trials Network (NCTN) or other NIH-supported National Trial Networks (Nationally funded Consortiums). NCTN groups bring together academic institutions and community-based cancer treatment centers throughout the United States and Canada to conduct cancer treatment trials and research. Because of the size of the NCTN groups, these clinical trials are designed to answer therapeutic questions that require a large group of study participants. The data for these trials are analyzed at the sponsor group s statistical center. These protocols enroll approximately 20,000 new participants per year into cancer treatment trials. These organizations are completely separate entities with separate leadership and research goals. The National trials that are Consortium-Sponsored originate and are conducted by an association of two or more individuals, companies, organizations or government (or any combination of these entities) with the objective of participating in a common activity or pooling their resources for achieving a common goal. The NCI Clinical Trials Network (NCTN) groups include: Alliance ECOG ACRIN NRG Oncology (NRG) Southwest Oncology Group (SWOG) The Nationally funded Consortiums include: ABTC (Adult Brain Tumor Consortium) AMC (AIDS Malignancy Clinical Trials Consortium) BMT CTN (Blood and Marrow Transplant Clinical Trials Network) CIBMTR (Center for International Blood Marrow and Transplant Research) CPN (Cancer Prevention Network) CRC (CLL Research Consortium) NABTC (North America Brain Tumor Consortium) NABTT (New Approaches to Brain Tumor Therapy) NANT (New Approaches to Neuroblastoma Therapy Consortium) NCBP (National Cord Blood Program) NMDP (National Marrow Donor Program) OCOG (Ontario Clinical Oncology Group) PBTC (Pediatric Brain Tumor Consortium) SCUSF (SunCoast Clinical Oncology Program Research Base of the University of South Florida) Externally Peer-Reviewed trials: These are trials supported by the NCI or NCI approved peer review organizations. Data for these trials are collected and analyzed at the NCI, DF/HCC, or another cancer center, depending on the trial. The investigational agents for these protocols may be supplied by the NCI. Included among the externally peer reviewed trials are those sponsored by: Cancer Therapy Evaluation Program (CTEP)

14 The Guide to Human Research Activities 14 NIH Grants (including SPORE, RO1, U01 etc) Agency for Healthcare Research and Quality (AHRQ) American Association of Cancer Research (AACR) American Cancer Society (ACS), (national office only) American Foundation for AIDS Research (amfar) American Institute for Cancer Research (AICR) California Institute for Regenerative Medicine (CIRM) Cancer Prevention Research Institute of Texas (CPRIT) Center for Disease Control and Prevention (CDC) Central Office of the Veterans Administration (VA) - excluding local awards and block grants Environmental Protection Agency (EPA) The Flight Attendant Medical Research Institute (FAMRI) Florida Biomedical Research Program (FBRP) Food and Drug Administration (FDA) Howard Hughes Medical Foundation Leukemia and Lymphoma Society Melanoma Research Alliance (MRA) Multiple Myeloma Research Foundation (MMRF) National Institute for Occupational Safety and Health (NIOSH) National Science Foundation (NSF) NY State Department of Health Wadsworth Center/NY State Stem Cell Science Program Prevent Cancer Foundation Prostate Cancer Foundation (PCF) Susan G. Komen for the Cure The California Breast Cancer Research Program (CBCRP) The California Tobacco Related Disease Research Program (TRDRP) US Army (DOD) special research program Institutional (Investigator-Initiated) Trials: These are trials that originate with a single cancer center. Most of these trials are conducted by DF/HCC medical staff, and the data for these trials are collected and analyzed at DF/HCC. Some are multi-center trials that originate at a collaborating cancer center. For these trials, DF/HCC enrolls subjects from DF/HCC centers but is not responsible for data collection or analysis. Investigator-initiated trials may receive some funding by pharmaceutical companies, foundations, or publically funded consortiums. The practices of all of these trials is dictated by the policies and procedures found in this guide, which are established by the DF/HCC offices and committees. Industrial Trials: These are trials designed and sponsored by a pharmaceutical or biotechnology company. Multiple institutions may collaborate on these trials. All data are sent to the sponsoring company or designated contract research organization (CRO) for analysis. The practices of these trials are outlined by the sponsor and/or CRO but still must meet DF/HCC standards and policies.

15 The Guide to Human Research Activities 15 Section 2: Centralized Offices and Committees Various aspects of the clinical trial process are dictated by local policies and procedures, federal regulations, and other guidelines that are enforced through DF/HCC offices and committees. All staff involved in conducting clinical trials, including both medical and non-medical specialists, are coordinated through two central administrative offices: The Office for Human Research Studies (OHRS) and the Office of Data Quality (ODQ). OHRS and ODQ collaborate with DF/HCC staff and human research procedure and policy committees to ensure the highest quality clinical research. The staff members within the ODQ also work with the study teams to ensure proper data collection and preparation for analysis. In addition, members of these offices serve on various human research procedure and policy committees. It is through the daily operation of these offices and regularly scheduled meetings of the research committees that DF/HCC is able to provide careful review of all ongoing scientific research and, ultimately, the care and protection of the research subjects. Centralized DF/HCC Offices 2.1 Office for Human Research Studies (OHRS) OHRS is the centralized DF/HCC office responsible for ensuring the regulatory compliance of human subject research. The office oversees all protocol related events that arise during human subject research, including the processes necessary for review, approval, and activation. OHRS is responsible for managing scientific committee (SRC) and institutional review board (IRB) reviews of research involving human subjects. OHRS coordinates review by ancillary and interested offices at all institutions at which the research will be conducted, including pharmacy, nursing, radiation safety, biosafety, and others.. OHRS staff consists of a senior director and four associate directors, an operations manager, human research coordinators (HRC), online communication coordinators, and administrative personnel. OHRS staff members play an important role in assisting the research staff with all regulatory aspects of the research study, from protocol submission and committee meetings to protocol or consent form revisions and continuing reviews. In addition to the regulatory aspects, OHRS provides the necessary documents and forms for the various stages of the clinical trial process. For additional information about the OHRS, please call the main number at (617) or refer to OHRS website at: General questions may also be sent to the OHRS address: ohrs@dfci.harvard.edu 2.2 The Office of Data Quality (ODQ) The Office of Data Quality (ODQ), formerly the Quality Assurance Office for Clinical Trials (QACT), provides clinical trials quality assurance and quality control resources for DF/HCC. Specific functions include: auditing and data safety monitoring, quality control of subject registration, timely submission of trial data, and other functions facilitated by the study teams at each institution. The Office is also responsible for supporting the Data and Safety Monitoring Process on behalf of the consortium. :

16 The Guide to Human Research Activities 16 Auditing. ODQ reviews and strengthens DF/HCC clinical trial processes through the audit program. It employs a continuous improvement approach that includes: proposing new policies based on audit findings; sending Audit Alerts to investigators and staff to highlight where general problem areas exist; and utilizing exit interviews as teaching opportunities for PIs and study teams. Auditing also has access to all Serious Adverse Events (SAEs) reporting to the IRB. Trials are selected for audit based on a variety of risk factors, including new principal investigators, multi-center, international site, and early phase trials. ODQ works closely with DF/HCC members who have not served as a PI before, and includes them in audits so that they may gain familiarity and understanding about the PI s role and responsibilities. Data Safety Monitoring. ODQ manages multiple clinical research committees that oversee data quality, notably the monthly Data and Safety Monitoring Committee (DSMC), semi-annual Data and Safety Monitoring Board (DSMB), monthly Audit Committee, and monthly Clinical Investigations Leadership Committee. Institutional Coordination. ODQ centrally facilitates NCI investigator registration and completes the initial submission to clinicaltrials.gov and CTRP to ensure registration compliance. It then performs routine checks to assure continued compliance with registration and posting requirements. Clinical Trials Education. The Office of Data Quality (ODQ) provides training and education in clinical trials to DF/HCC faculty and clinical research staff. This is accomplished through its Clinical Trials Education Coordinator. This position is specifically responsible for: 1) ensuring the development and management of instructor-led and computer based courses for investigators and study team staff which occur throughout the year; and, 2) coordinating the creation of materials that promote responsible conduct in research and research integrity. Services include: general and continuing education in human subject protections, including required initial and continuing certification through the CITI program; training in Good Clinical Practice (GCP) guidelines; and DF/HCC-specific training for researchers who are new to DF/HCC. Managing DF/HCC Standard Operating Policies and Procedures, and distribution of updated policies: The ODQ staff assists with the review and revisions of the policies needed to conduct DF/HCC clinical trials. Updated policies are presented to the Clinical Operations Leadership Committee and Research Administration Officials before being approved and posted on the DF/HCC website. For additional information about the ODQ, please call (617) or ODQ@partners.org. 2.3 The Clinical Trials Research Informatics Office (CTRIO) Clinical Trials Research Informatics. The Clinical Trials Research Informatics Office (CTRIO), is responsible for overseeing the identification, selection, implementation and support of informatics systems and tools to facilitate clinical trials at DF/HCC. The team provides innovative solutions to facilitate workflows that collect, standardize, store and analyze scientific data. The office provides direct support to the Protocol Review and Monitoring Process, the investigators and study teams, and other aspects of the clinical trials program. CTRIO maintains and supports all activities required to support clinical trials data. The Informatics solutions that support DF/HCC activities and the conduct of clinical research include: Oncology Protocol System (OncPro), a web-based portal that provides investigators and staff at all DF/HCC sites direct access to the latest approved version of protocol documents, informed consents, eligibility checklists, dose levels and other relevant protocol information.

17 The Guide to Human Research Activities 17 OHRS Submit, which facilitates electronic submission of regulatory forms by the study teams to the Office of Human Research Studies (OHRS). Research Protocol Subject Registration, which includes electronic confirmation of registration, facilitates connectivity to Epic at Partners and Children s Hospital Boston and the electronic Biologics Order Entry System. InForm, an electronic data capture product. Inform is used to design and develop case report form for investigator initiative trials. CTRIO also has the responsibility for implementing ecrf forms and training investigators/study teams on their use. OnCore, a comprehensive oncology focused clinical trials management system.. OnCore has improved the standardization and harmonization of clinical trials data across the consortium establishing the system as the source of truth. In addition to providing necessary information to such groups as the Clinical Trials Business Office and the Office of Data Quality, OnCore provides up-to-date information and critical tools to Research Programs, study teams and the clinical trials offices at member institutions for enabling efficient conduct of clinical trials. catissue. This tool is available to research teams for the management of biospecimens that are collected from subjects who have consented to banking of biospecimens for research use. The catissue tool was orginally enhanced to include functionality for site level security, and shipping and tracking functionality to facilitate the transfer of biospecimens to an off-site storage facility, which alleviated the lack of storage space issue faced by many researchers. Over the past five years, the system has replaced the homegrown biospecimen tracking application for all disease groups which included developing new workflows and implementing complex, disease-specific migrations. More recently the application was integrated with OnCore to receive protocol and subject registration information. Clinical Trials Offices 2.4 Dana-Farber Cancer Institute (DFCI) Clinical Trials Office (CTO) The mission of the DFCI Clinical Trials Office is to effectively support investigators and clinical research staff with the submission, coordination, and execution of DF/HCC research protocols involving human subjects. The CTO serves as a centralized DFCI resource for education, communication, and support related to regulatory compliance in clinical trials. The DFCI Clinical Trials Office provides regulatory support through the review of study protocols prior to submission, assistance with IND/IDE applications, audit preparation and CAPA development, project management, monitoring services, and the recruitment and orientation of clinical research staff within DFCI. The DFCI CTO also provides oversight for the Alliance and the Network Affiliates, ongoing support of clinical research activities at the DFCI satellite facilities, and development of a career pathway for staff including retention planning. The CTO works collaboratively with the OHRS and ODQ to ensure compliance with DF/HCC policies and procedures. The office is comprised of directors, senior managers, regulatory affairs specialists, clinical research managers, clinical research coordinators, monitors, project managers and administrative assistants. 2.5 Massachusetts General Hospital (MGH) Cancer Center Protocol Office (CCPO) The MGH Cancer Center Protocol Office was created in 1994, and it provides centralized data management and administrative management for MGH participation in each DF/HCC protocol. The administrative director

18 The Guide to Human Research Activities 18 of the MGH Cancer Center Protocol Office works closely with the DF/HCC Medical Director for Clinical Trials Operations and the ODQ director to ensure quality protocol management. The MGH Cancer Center Protocol Office works closely with the OHRS and the ODQ to comply with the regulatory aspects of every protocol and ensure proper subject registration and data collection. 2.6 Beth Israel Deaconess Medical Center (BIDMC) Cancer Clinical Trials Office (CCTO) The CCTO provides infrastructure and services to thirteen individual cancer disease programs. This group oversees 35 clinical research assistants, 11 research nurses, 2 regulatory specialists and a program coordinator who oversee nearly 500 clinical trials. The CCTO provides the following: Centralized coordination of new trial submission and oversight of all regulatory requirements; Hiring, training, and mentoring to the CCTO clinical research assistants and research nurses; Guidance and support to all disease groups within the CCTO; Collaboration with the DF/HCC with seats on the IRB, SRC and Operations Committee and acts as liaison with the greater BIDMC oncology, research and general communities. DF/HCC Committees 2.7 Clinical Investigations Leadership Committee (CLC) CLC provides a regular forum for the senior clinical investigations faculty and administrative leaders across the DF/HCC member institutions to discuss and resolve system-wide issues related to the conduct and support of clinical trials within DF/HCC. The committee reviews clinical investigations activities, processes, and systems, as well as DF/HCC issues that require senior-level, inter-institutional attention. The CLC advises the Center Director and Executive Committee regarding the various systems and processes related to the conduct of DF/HCC clinical trials. These processes and systems include, but are not limited to: System-wide, protocol-specific, or PI-specific issues that impact the appropriate conduct of clinical trials Organizational capabilities and resources related to clinical trials General issues related to trial design that impact the effective conduct of trials Inter-institutional policies and practices that impact the conduct of clinical trials Concerns that arise from clinical trial review, auditing and monitoring processes Issues that individual institutions have regarding the clinical investigations program Operational issues that require senior faculty input and institutional consideration on clinical trials issues 2.8 Clinical Trials Operations Committee (CLINOPS) CLINOPS is a component of DF/HCC s Clinical Research Unit, which is an NCI-approved Shared Resource. The purpose of CLINOPS is to review DF/HCC clinical trials operations and resolve identified clinical trial issues, facilitate inter-institutional communication, and develop and/or revise DF/HCC-wide clinical trials operating policies and procedures. Members include key representatives with clinical trials responsibilities

19 The Guide to Human Research Activities 19 from DF/HCC member institutions, including but not limited to such areas as nursing, pharmacy, information services, and data management. Minutes of the CLINOPS meetings are maintained by the ODQ. 2.9 Institutional Review Boards (IRBs) The mission of the DFCI IRB is to review research involving human subjects and to ensure that the risks and benefits of the research are appropriate and to ensure that there is full compliance with Federal regulations for the protection of human subjects in research. The DFCI IRB abides by the ethical standards set forth in the Belmont Report, and the regulatory provisions defined in 45 CFR Part 46 and 21 CFR Parts 50 and 56. The DF/HCC institutions have designated the DFCI IRB as their IRB of record to review cancer related research on their behalf. The DFCI IRB reviews all research involving human subjects and has the final authority to approve, require modifications in, or disapprove all research activities, including proposed changes in previously approved human subjects research. Senior Officials and department heads may not impede the review, approval and oversight process as implemented by the decisions by the IRB. The initial IRB review is based on a review of the protocol, consent and all other relevant documents. The IRB uses its expertise to determine whether the scientific merit of the research justifies the risk/benefit ratio. The IRB assessment of risks and anticipated benefits involves consideration of: Risks associated with the research, as distinguished from the risks of therapies the participants would receive if they were not participating in research Minimization of risks Probable benefits to be derived from the research Risks that are reasonable in relation to the benefits, if any, to subjects and the importance of the knowledge to be gained Information that potential subjects will be provided with an accurate and fair description of the risks or discomforts and the anticipated benefits Intervals of periodic review, and where appropriate, determination that adequate provisions are in place for monitoring the data collected The IRB determines the adequacy of the provisions to protect the privacy of subjects and to maintain the confidentiality of the data. Equally important, where the subjects are likely to be members of a vulnerable population (e.g., children, prisoners), the IRB must determine whether additional safeguards are in place to protect their rights and welfare. At the time of its initial review, the IRB must determine how often it should reevaluate the research project and set a date for its next review Scientific Review Committee (SRC) and Scientific Progress Review The Scientific Review Committees (SRC) review all cancer-related treatment trials involving adult subjects that are considered to involve greater than minimal risk. The SRC reviews the research for scientific merit, priority, and ability to meet accrual goals. This includes review for the novelty and importance of the therapeutic questions, the 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.

20 The Guide to Human Research Activities 20 The SRC review will also include an annual scientific progress review for all active clinical protocols. This review occurs after IRB review when results from the IRB continuing reviews will be provided to the SRC reviewer to facilitate identification of protocols that are not meeting accrual and/or scientific objectives. This review will be done by a single member of the committee and will focus on accrual data, scientific merit given changes in knowledge and discoveries over the past year and current prioritization status from the disease program. The Pediatric Scientific Review Committee (PSRC) reviews all trials involving pediatric participants. The PSRC reviews the novelty and importance of the therapeutic questions, the 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 pediatric protocols already underway. Scientific review occurs prior to IRB review. Protocols will not be referred to the IRB unless the investigator has responded to the condition(s) set by the SRC or PSRC and the response has been approved. For protocols involving both adult and pediatric participants, full board review will be conducted by the committee that represents the larger subject population (adult or pediatric) and a member from the smaller subject population will be asked to participate in the review of the trial at the convened meeting. Scientific Progress Review is conducted on active-enrolling clinical trials at least annually. This review is different from SRC review and IRB continuing review in that it focuses on accrual data, scientific merit given changes in knowledge and discoveries over the past year, and current prioritization status from the disease program. Scientific Progress Review is conducted by an individual member of the SRC. If the reviewer feels that the Scientific Progress is questionable, the study will be referred to the convened SRC for a full review of the protocols scientific progress to date.

21 The Guide to Human Research Activities 21 Section 3: The Study Team 3.1 Overall Principal Investigator (Overall PI) The overall PI has ultimate responsibility for the conduct of the research trial. The duties of the PI are outlined in FDA form 1572 and DF/HCC SOP RCO-102. The overall PI is responsible for all aspects of the protocol, including the following areas of clinical research: Coordinating the approval process, SRC/PSRC and IRB reviews, and department signs offs to approve activation Incorporating any necessary changes into the protocol through a formal amendment process, and obtaining SRC/PSRC and IRB approval prior to the implementation of such changes Informing fellows, nursing, pharmacy, and other staff about protocol requirements Overseeing all study team members Reporting trial results in a timely fashion By definition, overall PIs of designated high-risk trials must be physicians listed as DF/HCC professional medical staff (non-trainees). Protocols that originate at other institutions but are activated at DF/HCC must have a designated DF/HCC chairperson in addition to the overall PI at the originating institution. 3.2 Site Principal Investigator (Site PI) Each participating institution will have a designated site PI who is responsible for the conduct of the trial at that particular institution. The site PI is responsible for collaborating with the overall PI to ensure appropriate clinical and study conduct, including reporting of adverse events (AEs) as well as events that are unexpected and incidences of noncompliance. This term is a DF/HCC-specific term and may not be recognized by outside entities (i.e., the sponsor). For example, the sponsor may refer to a site PI as a Sub-investigator. Members of the study team in contact with the sponsor should familiarize themselves with the sponsor s terminology and adapt as necessary. 3.3 Collaborating Investigators (Co-investigators) Co-investigators are invited by the overall PI to participate in the research trial. They, too, must ensure appropriate clinical and study conduct by adhering to and performing the trial-specific procedures on behalf of the overall PI. 3.4 Biostatistician A biostatistician collaborates on various aspects of protocol development and reporting. She works closely with the team to ensure the relevance and appropriateness of statistics generated for the trial. For DF/HCC-initiated trials, the biostatistician will provide a design appropriate to the endpoints specified by the overall PI. 3.5 Research Nurse The research nurse manages the day-to-day operations of the clinical trial under the auspices of the overall PI. The research nurse facilitates the protocol process through a number of activities, such as verifying that the

22 The Guide to Human Research Activities 22 required tests are completed and that participants have been properly informed of the research to be conducted and have signed the appropriate consent form. She also assists with confirming eligibility, registering participants, monitoring participants for toxicity, making follow-up appointments with participants, and teaching other staff members about the protocol. A research nurse may also assist in preparing standard orders for protocol subject management. The research nurse is also responsible for staff education and participant/family education regarding the clinical trial. If protocol therapy is delivered by an affiliate or community hospital that has IRB approval to participate, it is the research nurse who educates and communicates with the health care providers to ensure protocol compliance. The research nurse may be involved in reporting AEs to the protocol sponsor, although it is the responsibility of the overall PI. 3.6 Study Coordinator The Study Coordinator, sometimes called Clinical Research Coordinator (CRC) or Clinical Research Associate (CRA), is an integral part of the study team and is responsible for reviewing research subject records, abstracting data, and completing the case report forms (CRFs) supplied by CTRIO (for in-house trials) or the sponsor (i.e., pharmaceutical company, NCI, cooperative group). The Study Coordinator works closely with the overall PI, the research nurse, and the study data analyst to perform protocol management for each trial. She has the primary responsibility of abstracting data from the medical records and other necessary sources. Study coordinators are involved with several areas of the clinical trial process, including protocol review, forms design, data collection, eligibility confirmation, and subject registration,.. Additional responsibilities may include scheduling participants, submitting reports, responding to requests for missing data and other queries, and preparing IRB submissions, such as amendments, continuing review reports, protocol violation and deviations, investigational new drug (IND) safety reports, and AE reports. For non-clinical research studies, the Study Coordinator works closely with the overall PI to manage the data and the implementation of research procedures. For some minimal risk research, the Study Coordinator may obtain informed consent from the subjects after determination by the IRB that it is appropriate. The Study Coordinator may be authorized by the IRB to review clinic lists and medical records in order to identify potential participants. These responsibilities must be specifically described in the protocol and approved by the IRB.

23 The Guide to Human Research Activities 23 Section 4 - Investigator and Study Staff Complaints and Suggestions When investigators and their staffs have suggestions or complaints regarding the human research protections, programs they are encouraged to contact one or more of the following individuals: Senior Director and/or Associate Directors of the OHRS IRB Chairs and/or Co-Chairs Director of the Office of Data Quality Director of the Clinical Trials Research Informatics Office Dana-Farber Cancer Institute Senior Vice President for Research Administration SRC Chairs and/or Co-Chairs Disease or Discipline-based Program leader Dana-Farber Cancer Institute Chief Executive Officer Institutional Official for any consortium institution These suggestions or complaints will be reviewed and considered. While investigators and staff may raise complaints or suggestions verbally, a written concern is recommended as it will elicit a written response via letter, memo or . Investigators and staff are encouraged to raise complaints or concerns in writing, via or memo.

24 The Guide to Human Research Activities 24 Section 5 - DF/HCC Standard Operating Procedures (SOPs) DF/HCC is committed to the safe conduct of clinical trials, and to ensuring high quality research across it s member institutions. To that end, DF/HCC has established Standard Operating Procedures (SOPs), which must be followed by Investigators and research personnel participating in cancer related research conducted directly or in coordination with DF/HCC. The research community receives notifications of all new and/or revised DF/HCC SOPs via the Research Listserv. New DF/HCC SOPs are circulated for a 14-day comment period prior to approval and posting. Members of the research community should review the draft documents and submit questions or requests for clarification before the policies are finalized. Draft DF/HCC SOPs are posted to the DF/HCC website before the final versions are published. DF/HCC SOPs become effective 30 days from approval unless otherwise indicated. Finalized SOPs are posted to the DF/HCC website. The Research Listserv is the mechanism used to disseminate important information to the DF/HCC clinical research community. The Research Listserv is updated when a clinical research staff member is hired or leaves their position. Information about signing up for the Research Listserv is described in Section 6.

25 The Guide to Human Research Activities 25 Section 6 - Research Communications 6.1 Research Listserv The OHRS and ODQ are responsible for the development and implementation of DF/HCC clinical research policies and procedures, and for providing clinical research support and guidance to the investigators and the research teams. It is important that the ODQ and OHRS maintain a current list of staff involved with clinical and non-clinical research. To be added to communications of critical research related information from OHRS and ODQ please sign up here: Research Staff leaving DF/HCC will automatically be removed from the list. 6.2 DF/HCC Membership and DF/HCC Website Access New DF/HCC members should also apply for DF/HCC membership and DF/HCC Website Registration. DF/HCC Membership Instructions are located on the DF/HCC website here: DF/HCC Website Registration Instructions are located on the DF/HCC website here:

26 The Guide to Human Research Activities 26 Section 7 - Required Human Subjects Protection and Good Clinical Practice Training Human Subject Protections (HSP) and Good Clinical Practice (GCP) training are required prior to participation in DF/HCC research. The following individuals (at a minimum) are required to complete HSP training: Investigators and research personnel who participate in the design, conduct or collection and reporting of data related to Human Subjects Research overseen by DF/HCC. This includes research that is deemed to be Exempt under the regulations or is considered to be Not Human Subjects Research (NHSR). Members of the DFCI IRBs and DF/HCC SRCs Key Personnel listed on an NIH grant The following individuals (at a minimum) are required to complete GCP training: Investigators and research personnel who participate in the design, conduct or collection and reporting of data related to Human Subjects Research overseen by DF/HCC, except those working exclusively on research that is deemed to be Exempt under the regulations or is considered to be Not Human Subjects Research (NHSR). Key Personnel listed on an NIH grant HSP and GCP training can be satisfied by completing the online Collaborative Institutional Training Initiative (CITI) educational program (described below). Other forms of human subject protection training may also be accepted. HSP and GCP re-education is required every three years. For questions regarding HSP or GCP training, please contact ODQ at ODQEducation@dfci.harvard.edu. 7.1 The CITI Program The CITI program consists of case-based learning of ethical concepts and regulations in a web-based learning environment. Experts in bioethics and the IRB community developed the program. The modules include reading material that can be viewed on screen or printed, followed by a brief online quiz. The format is openbook. The CITI program offers a GCP course as well as four HSP courses. The courses are: Biomedical HSP Course Social/Behavioral HSP Course IRB-Exempt/Not Human Subject Research HSP Course Combined Social/Behavioral and Biomedical HSP Course Good Clinical Practice (GCP) The specific HSP course required depends on the role of the registrant. Individuals who overlap two areas (e.g. therapeutic clinical and behavioral research) need to complete the Combined Social/Behavioral and Biomedical HSP Course in order to do research in both areas or to review studies in both areas.