The Guide to Human Research Activities 1

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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

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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

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7.3 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 10.2.1 Pre-Clinical 10.2.2 Phase I 10.2.3 Phase II 10.2.4 Phase III 10.2.5 Phase IV 10.2.6 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 Version: March 2017

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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 20.10 Response to Committee Requests 20.11 Claim of Exemption 20.12 New Submission Flow Chart 20.13 Protocol Activation and Distribution

21: Continuing Review

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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 25.10 PI-initiated/IND Holder Reporting Requirements 25.11 PI-initiated/Sponsor Holds IND Reporting Requirements 25.12 Industry-sponsored (Investigational) Reporting Requirements 25.13 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

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27.6 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 28.10 Industry-led and Cooperative-group Registration 28.11 Non-patient Volunteer Registration 28.12 Electronic Confirmation of Registration 28.13 After-hours Registration 28.14 Removing a Participant from a Research Study 28.15 Protocol Closure Notification 28.16 Protocol Completion/Termination Notification 28.17 Reports Available from the Clinical Trials Research Informatics Office 28.18 Protocol Accrual Monitoring 28.19 Case Report Form (CRF) Design 28.20 Documentation and Storage of Data 28.21 Accrual-monitoring Program 28.22 Internal Auditing 28.23 DF/HCC Data and Safety Monitoring Board (DSMB) 28.24 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

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32.2 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 34.10 Final Study Reports 34.11 Withdrawal of an IND Application 34.12 General Responsibilities of the Investigator-Sponsor 34.13 Selecting Participating Investigators and Monitors 34.14 Informing Participating Investigators of New Observations 34.15 Reviewing Ongoing Investigations 34.16 Record Keeping and Record Retention 34.17 Inspection of Records and Reports 34.18 Disposition of Unused Investigational Drug 34.19 General Responsibilities of Participating Investigators 34.20 Control of the Investigational Drug 34.21 Participating Investigator Record Keeping and Record Retention 34.22 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

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35.6 Staff Training 35.7 Central Participant Registration 35.8 Adverse Event Reporting 35.9 Data Collection 35.10 Quality Assurance 35.11 Site Communication 35.12 Drug Ordering 35.13 Inter-institutional Agreement/Contract 35.14 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

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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 2005. 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

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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) http://www.dfhcc.harvard.edu/

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) www.bidmc.org

 Boston Children’s Hospital (BCH) www.childrenshospital.org

 Dana-Farber Cancer Institute (DFCI) www.dana-farber.org

 Brigham and Women’s Hospital (BWH) www.brighamandwomens.org

 Harvard Medical School (HMS) www.hms.harvard.edu

 Harvard School of Public Health (HSPH) www.hsph.harvard.edu

 Massachusetts General Hospital (MGH) www.massgeneral.org

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-

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cation, training, site assessments, IRB and other regulatory approvals, study activations and auditing. Net- work 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

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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.

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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)

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 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.

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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) 632-3029 or refer to OHRS website at: http://www.dfhcc.harvard.edu/clinical-research-support/office-for-human-research-studies-ohrs/

General questions may also be sent to the OHRS e-mail address: [email protected]

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. :

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● 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) 632-3761 or email: [email protected].

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.

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 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 home- grown 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)

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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

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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.

2.10 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.

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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.

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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

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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.

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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 e-mail. Investigators and staff are encouraged to raise complaints or concerns in writing, via email or memo.

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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 email 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.

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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 email communications of critical research related information from OHRS and ODQ please sign up here: http://www.dfhcc.harvard.edu/clinical-research-support/office-for-human-research-studies- ohrs/oncology-protocol-system-and-ohrs-submit/

Research Staff leaving DF/HCC will automatically be removed from the email 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: http://www.dfhcc.harvard.edu/membership/applying-for-membership/

DF/HCC Website Registration Instructions are located on the DF/HCC website here: https://www.dfhcc.harvard.edu/no_cache/membership/login/l/1/

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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 [email protected].

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 “open- book.”

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.

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Each CITI module has a short quiz. You must achieve a compiled score of 80% to pass the course.

Completion of the initial CITI Basic program takes about four to six hours. Completion of the CITI Refresher takes approximately three hours. Users are not required to complete the exam in one sitting. Please note that registrants who begin a course but do not log in again for 30 days will be deleted from the system and will have to re-register.

Upon completion of all required modules, print or download a Course Completion Report as evidence that you have met the requirements. It is important to keep a copy for your records.

You can register to take the CITI course at www.citiprogram.org. If you encounter technical issues, please contact the CITI Support Desk at [email protected].

7.3 DF/HCC Human Subject Protection and Good Clinical Practice Training Lists

Individuals who complete the required HSP and GCP training are responsible for providing a training completion certificate to ODQ so it can be added to the Clinical Trials Management System (CTMS) OnCore. The DF/HCC HSP and GCP Training List will be generated from OnCore and will be posted on the DF/HCC website as a reference for researchers.

Individuals are responsible for ensuring their training information is current in OnCore by providing updated certificates of completion to ODQ for entry into OnCore. Training Certificates should be emailed to: [email protected]

7.4 Continuing Human Subjects Protection and Good Clinical Practice Trainings

Continuing Human Subject Protection and Good Clinical Practice training is required every three years. Individuals must complete the CITI Refresher courses, or another approved HSP or GCP training program, within the three-year anniversary of their previous training date.

Subsequent recertification is required within three years of the previous re-certification anniversary.

7.5 Expiration of Human Subjects Protection and Good Clinical Practice Trainings

It is the Overall Principal Investigator’s responsibility to make sure the Human Subject Protection and Good Clinical Practice training requirements are met by all individuals listed on the protocol. Lack of current HSP and/or GCP training by an individual listed on a protocol may result in the temporary suspension of research activities for that specific individual.

The following actions will be taken if HSP and/or GCP training expires:  If the Overall PI of a study fails to meet the training requirement(s), the DFCI IRB will temporarily close the study until the training requirement(s) are met.  If the Site Responsible PI of a study fails to meet the training requirement(s), the DFCI IRB will temporarily close the study at that site until the training requirement(s) are met.  If a co-investigator of a study fails to meet the training requirement(s), the DFCI IRB will temporarily remove that co-investigator from the study until the training requirement(s) are met.

Research staff will be reinstated once they complete an accepted continuing education course and the overall PI or designee files the appropriate paperwork with OHRS to add the individual back to the study.

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Section 8 - Federal Guidelines for Research Involving Human Subjects

As a Federally-designated comprehensive cancer center, DF/HCC is governed by Federal and state regulations, local policies and procedures and other guidance.

The DFCI IRB is regulated by the Code of Federal Regulations as found at 21 CFR Parts 50 and 56, as well as the Code of Federal Regulations as found at 45 CFR Part 46, Subpart A (The Common Rule). Regulations that govern investigational new drugs (INDs) are found in 21 CFR Part 312; biologics are found in 21 CFR Part 600 and devices are found in 21 CFR Part 812. There are other regulations governing devices and other aspects of human subject research that the IRB must adhere to as applicable. DFCI has an assurance on file with the Department of Health and Human Services (DHHS), otherwise known as a Federalwide Assurance (FWA) that sets the standard for ethical review of all research. The OHRS and IRB ensure that these standards are met.

The DFCI IRB assurance number is FWA00001121.

The Assurance states that all research involving human subjects that is conducted by DFCI staff or by researchers who fall under the purview of the DF/HCC, or on DFCI premises or under its sponsorship, whether supported by Federal funds or not, must be reviewed and approved by the DFCI IRB. Once approved, these trials must be re-reviewed by the IRB at least annually. This policy also applies to protocols sponsored by DF/HCC staff conducting research at other hospitals, institutions, or community groups, or any other areas outside the DF/HCC. Individuals not affiliated with the DF/HCC proposing trials using DFCI patients or patient families as research subjects must have a DF/HCC sponsor investigator and abide by these policies and procedures.

The Federal Regulations set out the specific criteria that should be considered by the IRB in determining whether or not to approve research involving human subjects. The following is excerpted directly from the regulations (45 CFR 46.111):

1. Risks to subjects are minimized (by using procedures which do not cause unnecessary risk and , when possible, by using procedures already being performed on subjects for diagnosis and treatment); 2. Risks to subjects are reasonable in relation to anticipated benefits. In evaluating risks and benefits the IRB should consider only those risks and benefits that may result from the research as distinguished from risks and benefits of therapies subjects would receive even if not participating in the research. The IRB should not consider possible long-range effects of applying knowledge gained in the research; 3. Selection of subjects is equitable. In making this assessment the IRB should take into account the purposes of the research and the setting in which the research will be conducted, and should be particularly cognizant of the special problems of research involving vulnerable populations, such as children, prisoners, pregnant women, mentally disabled persons, or economically or educationally disadvantaged persons; 4. Informed consent will be sought from each prospective subject or the subject’s legally authorized representative, in accordance with and to the extent required by 46.116; 5. Informed consent will be appropriately documented, in accordance with and to the extent required by 46.117; 6. Adequate provision is made for monitoring data collected to ensure the safety of subjects; 7. Adequate provision is made to protect the privacy of subjects and to maintain the confidentiality of data; Version: March 2017

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8. Additional safeguards have been included in the study to protect the rights and welfare of subjects when some or all are likely to be vulnerable to coercion or undue influence (such as children, prisoners, pregnant women, mentally disabled persons, or economically or educationally disadvantaged persons.)

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Section 9 - Degree of Risk

Federal regulations define risk as the probability of harm or injury (physical, social, or economic) occurring as the result of participation in a research study. Both the probability and magnitude of possible harm may vary from minimal to significant. The risks to participants should be justified in relation to the anticipated benefits. The IRB must determine that risks are managed to the extent possible consistent with sound research design.

9.1 Minimal Risk

Minimal risk protocols are those for which the anticipated risks are no greater than those ordinarily met in daily life, or during the performance of routine physical or psychological examinations (e.g., blood draw, urine sample, anonymous survey. Minimal risk protocols may or may not require review by a full IRB.

Examples of minimal-risk protocols include but are not limited to:

● Data collection from medical record reviews, laboratory test results, and pathology records ● Questionnaires or surveys that meet the no-greater-than-minimal-risk definition ● Laboratory investigation using human subject samples such as limited amounts of blood drawn from research participant’s collection of discarded tissues or other samples.

DFCI IRB policy does not allow investigators to obtain samples (e.g., blood) for minimal risk trials from employees who are under their direct supervision.

9.2 Greater than Minimal Risk

Greater than minimal risk protocols place participants at higher risk than the risks ordinarily met in daily life or during the performance of routine physical care and include such examples as chemotherapy, taking of bone marrow or a biopsy. These protocols usually involve investigational drugs, new treatment methods or invasive procedures, or are clinical trials that will yield generalizable knowledge about the disease or subject population.

Pediatric research requires a more detailed analysis of the risks by the IRB. Please refer to the OHRS information sheet “Additional Protections for Children” on the OHRS website.

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Section 10 - Research Methods for Drug Studies

Research involving human participants at the DFCI and conducted under the auspices of the DF/HCC is governed by federal regulations found at 45 CFR Part 46 and 21 CFR Parts 50 and 56. The latter set of regulations governs FDA- regulated research involving drugs, devices and biologics.

The HHS regulations codified in 45 CFR Part 46 define research as follows:

Research means: a systematic investigation, including research development, testing and evaluation, designed to develop or contribute to generalizable knowledge. Activities meeting this definition constitute research for purposes of this policy, whether or not they are conducted or supported under a program that is considered research for other purposes. For example, some demonstration and service programs may include research activities.

Under the federal regulations, human subjects are defined as living individual(s) about whom an investigator conducting research obtains data through intervention or interaction with the individual; or identifiable private information

The FDA regulations use the term “clinical investigation” and define it as follows:

Clinical investigation means any experiment that involves a test article and one or more human subjects and that either is subject to requirements for prior submission to the FDA under section 505(i) or 520(g) of the act, or is not subject to requirements for prior submission to the FDA under these sections of the act, but the results of which are intended to be submitted later to, or held for inspection by, the FDA as part of an application for a research or marketing permit. The term does not include experiments that are subject to the provisions of part 58 of this chapter, regarding non-clinical laboratory trials.

10.1 The Drug Development Process

The drug development and approval process relies heavily on clinical trials. When reviewing new drugs/devices/biologics for approval, the FDA is required by law to determine that such agents are safe and effective for specific uses.

Before an investigational agent can be introduced to humans, it must first show promising results in laboratory and/or animal experiments. After completing such experiments, a sponsor submits an Investigational New Drug (IND) application to the FDA. Technically, if the FDA requests no additional information within 30 days after submission, the sponsor may initiate clinical trials with human participants. Although technically correct, the DF/HCC does not recommend doing so. It is in your best interest to establish that the FDA has in fact received and reviewed your materials.

If the trials and data illustrate safety and effectiveness, the sponsor (or sponsor and PI) will then submit a new drug application (NDA) or biologics license application (BLA) to the FDA. Marketing of the new agent may begin once approval by the FDA is granted.

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10.2 Types of Trials This section provides descriptions of the different phases and types of research trials.

10.2.1 Pre-clinical

In pre-clinical trials, a drug’s toxic and pharmacological effects are evaluated through in vitro and in vivo experiments. Through such trials, researchers gather information about drug absorption, metabolism, and rate of excretion from the body.

10.2.2 Phase I

These trials represent the first or early use of the drug in humans. The major objective of a Phase I trial is to determine the maximum tolerated dose (MTD) of the trial agent given in this schedule for humans while identifying the dose-limiting toxicity (DLT). In a single Phase I trial, eligible subjects may have a variety of cancer types. The Phase I design may also be used to evaluate new treatment schedules or combinations of established drugs and/or radiation.

10.2.3 Phase II

Phase II trials are done after the MTD has been determined by the Phase I trial. The major objective is to determine the efficacy of an agent for a given disease or group of diseases. Typically, all subjects receive the same dose of drug (e.g., the MTD defined by the Phase I trial) or undergo the same intervention. Often, a number of Phase II trials are done utilizing different dosing schedules of the same agent.

Alternatively, randomized phase II studies may compare different dosing schedules or regimens to try to determine which is most promising for further evaluation. The most promising regimen, if shown to be sufficiently active, is then used in the subsequent Phase III trial.

Phase II trials also collect additional toxicity information.

10.2.4 Phase III

The major objective of Phase III trials is to compare the efficacy of at least two treatments. This is typically the current standard therapy versus one or more experimental treatment groups. The usual primary purpose of a phase III study is to attempt to determine whether a treatment approach provides a survival advantage as compared with the other(s). Alternatively, if they produce equivalent survival, one might be preferred because it is associated with less toxicity.

10.2.5 Phase IV

Called post-market approval trials, these trials take place after a new agent has been approved for use and marketing by the FDA. Phase IV trials are designed to further evaluate the long-term safety and effectiveness of a treatment. These trials are less common than Phase I, Phase II, and Phase III trials and sometimes are required by the FDA.

10.2.6 Multi-Modality Trials

Combination trials are done when two or more modes of therapy, such as surgery, chemotherapy, and immunotherapy, are used in combination in an attempt to evaluate potential benefits of combined modality treatment of disease.

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Section 11 - Expanded Access to Investigational Treatment

The following are not considered clinical trials but instead offer expanded access to investigational treatment to those participants who have not benefited from conventional therapy. Please refer to the OHRS Information Sheet “Single Patient IND and Emergency Use of a Test Article.”

11.1 Emergency Use

The DFCI IRB allows the emergency use of an investigational drug or biologic if the FDA requirements for emergency use are met.

The emergency use provision in the FDA regulations is an exemption from prior review and approval by the Institutional Review Board but does require obtaining informed consent from the participant, and may not be used unless each of the following conditions exist:

1. The patient is in a life-threatening or severely debilitating situation;

2. There is no standard acceptable treatment available; and

3. There is not sufficient time to obtain approval from the Institutional Review Board.

Life-threatening means diseases or conditions where the likelihood of death is high. The criteria for life- threatening do not require the condition to be immediately life threatening or to immediately result in death. Rather, the participants must be in a life-threatening situation requiring intervention before review at a convened meeting of the Institutional Review Board is feasible. (Please note: The DFCI IRB usually meet two – three times per week.)

Even in an emergency situation, the investigator is required to obtain informed consent from the participant or the participant's legally authorized representative.

When these instances arise, the following must occur:

1. The investigator must contact the Senior Director or Associate Directors of OHRS; 2. OHRS will review the applicable regulatory requirements and institutional requirements with the investigator; 3. The OHRS information sheet outlining regulatory and institutional policies and procedures will be provided to the investigator; 4. If the use of the test article does not meet the regulatory requirements, the investigator will be informed by OHRS that she may not proceed with the emergency use; 5. If the use does meet the regulatory requirements, the investigator will be asked to submit a protocol and consent form for review by OHRS staff; 6. The investigator will then receive documentation from OHRS (e.g. an email communication) that the request has been cleared and will be given a protocol number so that pharmacy can dispense and nursing can administer the investigational agent; 7. The investigator must obtain permission from the sponsor; 8. The emergency use of an unapproved investigational drug or biologic requires an IND. However, the FDA may authorize shipment of the drug or biologic in advance of the IND submission when there is insufficient time. 9. The investigator will be advised by OHRS to submit a report of the emergency use for review by convened IRB. The report will be placed on the next available IRB agenda. Version: March 2017

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FDA contacts for obtaining an Emergency IND are available at http://www.fda.gov/RegulatoryInformation/Guidances/ucm126491.htm.

11.2 Treatment IND (Single Patient IND)

Some drugs that have not yet been approved by the FDA for marketing may be appropriate to use in the treatment of patients who are not in clinical trials. The FDA has developed a system to facilitate the availability of promising new drugs to desperately ill patients as early as possible in the drug development process, before general marketing begins, and to obtain additional data on the drug’s safety and effectiveness.

For the purposes of the DFCI IRB, “treatment use” of a drug includes the use of the drug for diagnostic purposes. When an investigational drug meets the criteria listed below it will be submitted to the FDA as a “treatment protocol” or “treatment IND”. Please refer to the OHRS Information Sheet “Single Patient IND and Emergency Use of a Test Article.”

Criteria: 1. The drug is intended to treat a serious or immediately life-threatening disease; 2. There is no comparable or satisfactory alternative drug or other therapy available to treat that stage of the disease in the intended patient population; 3. The drug is under investigation in a controlled clinical trial under an IND in effect for the trial, or all clinical trials have been completed; and 4. The sponsor of the controlled clinical trial is actively pursuing marketing approval of the investigational drug with due diligence.

When the investigator determines that she is in this situation the following must occur: 1. Notify the Senior Director or Associate Directors of OHRS that a treatment IND will be submitted to the FDA; provide copies of the documentation to be submitted; 2. The study documents, including the protocol and informed consent form, will be placed on the next available convened meeting of the IRB for review and approval; 3. The investigator must obtain permission from the sponsor; 4. The investigator will be required to submit FDA documentation to the OHRS for inclusion in the study’s file immediately after it becomes available. This is required for activation; 5. The treatment IND will be subject to all the requirements of human subjects research including reporting of unanticipated problems to the IRB, safety reports to the FDA, informed consent, and continuing review to highlight a few of these requirements.

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Section 12 - Tissue/Data Collection and Record Reviews

The section discusses research methods such as tissue banking and medical chart review. Please also refer to OHRS information sheets:  DFCI IRB Requirements Relating to the Honest Broker in Biobanking  Instructions on the Collection and Sharing of Data and Tissue Specimens  Guidelines for Writing a Specimen/Data Collection and Banking Research Protocol

12.1 Banking Specimens and/or Data for Future Research

Human tissue samples are valuable sources of information for research purposes. Whether collected prospectively or retrospectively, all research involving specimen and/or data banking at DF/HCC requires review by the IRB. The Common Rule regulations found at 45 CFR 46 et seq apply to research of this type.

A new project application and protocol should be submitted describing the bank to be created. The following information should be included:

 The types of specimens and/or data to be collected;  The types of research planned for the specimens;  A description of the process for identifying potential participants (specimen donors);  A description of the process for obtaining consent (or an explanation, based on the regulations, that a waiver of consent will be requested);  A description of where the specimens and/or data will be housed and who will be responsible for overseeing the bank;  A discussion as to how long the specimens and/or data will be kept.  If there are any plans to share the specimens or data with other researchers, this must be defined in the protocol and consent document. This should include a description of how this access will be tracked. The protocol must include a Usage Agreement to be signed by the collector PI and the recipient investigator that sets out the conditions for use of the data or specimens; and  The repository’s policy and procedures concerning the return of individual research results to participants.

With regard to the consent document, the above information should be clearly and simply explained. In all cases, contact information should be included, as well as contact information for the IRB and a brief discussion of any risks to privacy and confidentiality and any physical risks that may be at issue. Participants must also be informed that current and future care as well as current and future participation in clinical trials will not be affected in any way based on their decision of whether or not to participate in research involving the collection of tissue specimens or clinical data. The following information should be included in the consent document:

 An explanation of how confidentiality will be maintained  The rights and limitations of participants to require destruction of their samples and/or associated data at a future date  The rights and limitations of participants to require that their samples and/or associated data be stripped of any identifying information  What identifying information will be available to other researchers if their samples and/or associated data are part of a registry or database

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12.2 Access to Banked Tissue/Data by Other Investigators

Access to banked tissue and/or data by other investigators depends upon many factors, including whether identifiable information is being sought, and what the approved banking protocol permits in terms of release of tissue and/or data. The IRB encourages usage agreements in approved banking protocols that permit release of coded or anonymous tissue or data. The sharing of identifiable tissue or data would require IRB review and approval of a new protocol.

Investigators should be aware that IRB approval does not guarantee access to any tissue or data bank. Permission from the investigator(s) or the committee that has oversight of the specimen bank is also required and should be obtained prior to submission to the IRB. For more information, see the section on Privacy and Confidentiality.

12.3 Research Involving Previously Banked Tissue

Research that involves existing pathological or diagnostic specimens may be exempt from IRB review. Pursuant to 45 CFR 46.101(b), research involving existing data, documents, records, pathological specimens, or diagnostic specimens may be exempt from IRB review if the sources are publicly available or the information will be recorded in such a manner that participants cannot be identified (directly or through identifiers linked to the subjects). Secondary research that does not involve any interaction with the participants, and which involves the use of deidentified samples may also be determined to not be human subjects research. Researchers themselves cannot make such a determination. All research activities must be reviewed by OHRS. See the OHRS sheet “Request for Exemption or Determination that Activity is Not Human Research” for more information on making such a request. If an investigator involved in the collection of the samples is also involved with the secondary research, the research cannot be deemed exempt or not human subjects research because it is presumed that they have access to identifiable information. In that situation, the study team should use the New Project Application for use of previously collected tissue samples.

12.4 Research Involving Record Reviews

Another source of information in research that may not involve direct interaction with research participants is the review of previously collected medical information (i.e., medical charts, X-rays, billing records, disease registries, and designated databases). Trials involving review of such information do require IRB review and approval. The IRB may authorize a waiver of informed consent. For the criteria necessary for a waiver of the informed consent requirement, see the sections on IRB Waiver of Informed Consent and Waiver of Informed Consent and Authorization for Research.

A new project application should be submitted describing the data to be collected. The following information should be included in the application:  Purpose or hypothesis being studied  Types of analyses to be conducted  Source(s) of the medical information  Statement that the chart information to be used in the trial already exists, if applicable

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 Statement that some or all of the chart information that will be used will be from data sources created in the future (e.g., after the date of IRB approval), if applicable  Inclusive dates of medical record information that will be used in the trial  Description of those who will have access to the collected information  Description of how long the information will be kept and plans for destroying the information upon completion of the trial  List of specific variables that will be used from the medical record chart  Plans for maintaining the privacy and confidentiality of the information  Plans for coding, or de-identifying, the information

Upon review of the proposed research, an IRB member may determine the trial is exempt from IRB review (i.e., if the data set contains no identifiers or the data are publicly available). Please the OHRS Information Sheet on Request for Exemption or Determination That Activity is Not Human Subject Research for further information. Otherwise, the study may be eligible for expedited IRB review.

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Section 13 - Medical Devices

13.1 Definition

A medical device is defined as an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including a component part or accessory which is:

1. Intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or other animals; or 2. Intended to affect the structure or any function of the body of man or other animals, and which does not achieve any of its primary intended purposes through chemical action within or on the body of man or other animals and which is not dependent upon being metabolized for the achievement of any of its primary intended purposes.

Medical devices include, but are not limited to, pacemakers, dialysis equipment, breast implants, bandages, thermometers, glucose pumps, wheelchairs, scalpels and contact lenses.

A “device” is any device used for clinical research that is supplied by the sponsor of the trial for use in an IRB approved protocol. It is the joint responsibility of the investigator and the Institutional Review Board to ensure that an IDE from FDA is in place if necessary for a medical device or an in vitro diagnostic. The investigator makes the initial determination whether to apply to FDA for an IDE. In the event that an investigator declines to contact FDA about the need for an IDE, the IRB may, in its discretion, require the investigator to contact FDA and obtain a determination regarding the need for an IDE as a condition of IRB approval. In addition, the IRB will make the regulatory determinations regarding whether a device constitutes a significant or non-significant risk device as appropriate.

 Significant risk (SR): A SR device study is defined by the regulations (21 CFR 812.3) as one that presents a potential for serious risk to a participant. In order to conduct a SR study, the sponsor must submit an IDE to the FDA as well as obtain IRB approval prior to study initiation.  Non-significant risk (NSR): A NSR study, on the other hand, does not. In order to conduct an NSR study, an investigator must first submit a proposal to the IRB. If the IRB concurs with the investigators/sponsor’s NSR determination, the study may be initiated upon their final approval

13.2 Ordering

The Principal Investigator identified on the IRB approved protocol will be the physician under which the investigational device will be ordered. The device will be ordered as per the sponsor’s instructions. The order will supply all information required to accurately fill the order and permit proper recording.

13.3 Storage

All investigational devices will be stored under control of the Principal Investigator. This may be in the PI’s office or in a specialized laboratory such as the Cell Manipulation Laboratory.

13.4 Authorization

The physician will obtain formal written patient consent and authorization prior to using any investigational device. This consent process and document must have documented IRB approval.

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The Principal Investigator, or designated specialized laboratory, will be responsible for dispensing the investigational device per protocol and department policies and procedures. Each protocol has its own device supply. The transfer of devices between protocols is prohibited. If this is required, the sponsor of the trial must be notified and approval granted. For NCI-sponsored device trials, if under extenuating circumstances devices are transferred between studies, a device transfer form must be completed. All pertinent device accountability records will be maintained by the PI or designated specialized laboratory.

13.6 Destroying

Used investigational devices will be destroyed according to the department’s waste handling procedures. Any unused/unopened investigational devices will be returned to the trial sponsor for destruction, unless authorized by the trial sponsor to destroy on site.

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Section 14 - Behavioral/Social Science Research

Behavioral and social science research involves the study of human behavior, quality of life, anthropology, epidemiology, and the effects of educational and interventional efforts. In order to collect behavioral data, researchers employ such study methods as surveys, interviews, questionnaires, review of existing records, observation and/or psychological and social interventions. The utilization of these research methods may present some ethical concerns such as psychological and social risks, deception and confidentiality. All of this is taken into account during the IRB review. When designing and conducting behavioral and social science research, investigators should:

1. Minimize the potential for stress, discomfort or other harms; 2. Respect participants’ privacy and minimize intrusion; 3. Design mechanisms to protect confidentiality of data; 4. Guard against factors leading to undue influence.

Behavioral and social science research may present more than minimal risk and thus be subject to review by the convened IRB. Some behavioral and social science research may be exempt from IRB review under 45 CFR 46.101(b) or may be eligible for expedited IRB review pursuant to 45 CFR 46.110. The DF/HCC human research population often warrants heightened scrutiny by the IRB.

The OHRS website has a variety of information sheets and resources for investigators conducting social/behavioral research. In addition, DFCI is a member of the Harvard Catalyst CTSA and its website has many resources for investigators.

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Section 15 - Vulnerable Populations

People are autonomous when they can deliberate personal goals and act accordingly. Some individuals may have limited autonomy and be unable to give informed consent. Additional protections may be warranted in these instances.

15.1 Inclusion of Children as Participants in Research

In cases where the investigator plans to involve children as research participants, the following will be considered:

1. Whether or not the research represents minimal risk to the child. The IRB will consider if it is possible to obtain assent from the children who will take part in the study and whether at least one parent or guardian is available to give permission for the child to take part in the research. The IRB will review such issues as the relative risk to the population of children under review. If these risks were perceived to be the risks that are encountered by children in ordinary life, the committee or IRB member would find and document this information in the study’s approval.

2. Whether the research is greater than minimal risk but offers the prospect of direct benefit. In cases where the research being proposed is of greater than minimal risk to the child but may offer the prospect of direct benefit to the child, the IRB will consider whether or not some, all or none of the children are capable of giving assent and that permission will be sought from both parents as they are available. The IRB will also consider that the research being proposed has an anticipated benefit that is at least as favorable as that of the alternative approaches. The committee would base this decision on the type of research being proposed. For example, studies about potential new treatments for disease may indeed propose the opportunity for direct benefit to the children in question. IRB determinations will be documented in the minutes of the IRB or otherwise in the IRB documents.

3. Whether the research is greater than minimal risk and does not offer the prospect of a direct benefit. When the research being proposed offers greater than minimal risk and no prospect of direct benefit the IRB will consider whether or not some, all or none of the children are capable of giving assent and that permission will be sought from both parents as they are available. The IRB will also consider whether the proposed research is likely to yield generalizable knowledge about the disease or disorder. For example, studies about potential new treatments for disease may indeed propose the opportunity for direct benefit to the children in question, especially when this disease has little or no treatment options. The IRB determinations will be documented in the minutes of the IRB or otherwise in IRB documents.

Requirements for permission of parents or guardians and for assent by children While reviewing studies that involve children, the IRB will assess the investigator’s plan for obtaining permission from parents/guardians as well as plans for obtaining assent from the children. In cases where the studies are of minimal risk to the child, the permission of one parent may be sufficient. In cases where the research presents more than minimal risk to the child but there is the prospect for direct benefit, the IRB may also find it sufficient to ask for permission from one parent. When the IRB reviews studies that involve more than minimal risk for the child and do not hold out the prospect for direct benefit but do offer an opportunity to learn more about the disease under study, the IRB will require the permission of both parents when both are reasonably available. Version: March 2017

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In making this determination the IRB will work with the investigator to determine whether or not the permission of both parents should be sought, when both parents are reasonably available or when it is sufficient to obtain permission from one parent. Investigators should refer to the OHRS Information Sheet “Additional Protections for Children.” The DFCI IRB requires that assent be obtained from children ages 10 to 17 barring unusual circumstances.

15.2 Pregnant Women and Fetuses in Research

Generally, DF/HCC institutions do not perform cancer-related research that targets pregnant women. In rare situations where this would be the case, the IRB will consult with experts in this area. The IRB will also perform a careful review of the regulations governing pregnant women in research.

Some researchers do perform research involving tissue from dead fetuses. In these cases, the investigator is asked to confirm that the collection of this tissue was done in accordance with Massachusetts state law, that fetal tissue was not collected from women who are under the age of 18 and that no woman was induced to abortion for the purposes of the research.

15.3 Cognitively Impaired Persons Involved in Clinical Research

Individuals in a wide variety of situations may have impaired decision-making capacity. Impaired capacity is not limited to individuals with neurologic, psychiatric, or substance abuse problems; for example, impairment may occur at times of great stress. Understanding and identifying the range of, and fluctuations in, decision- making capacity are therefore the first steps to providing appropriate protections in the clinical research setting.

While limited decision-making capacity should not prevent participation in research, the IRB is committed to providing additional scrutiny and protections for studies involving this population. The Department of Health and Human Services (DHHS) does not have specific regulations to govern research with cognitively impaired participants, unlike research involving children, prisoners, pregnant women, and fetuses. However, the federal regulators offer the following “Points to Consider” to assist the IRB and clinical investigators in their effort to protect participants in research who are, may be, or may become decisionally impaired. The DFCI IRB has adopted these “Points to Consider” as the guideline for all its clinical research studies involving the decisionally impaired.

Potential and actual research participants, especially those with permanent or transient cognitive impairments, may find it difficult to understand the difference between research and treatment, and to understand researchers' multiple roles, making "therapeutic misconceptions" particularly problematic and possibly creating confusion among participants and their families.

It is essential that the consent process clearly indicate differences both between individualized treatment and research and between clinician and clinical investigator.

An individual's capacities, impairments, and needs must be taken into account in order to develop practical and ethical approaches to enable them to participate in research. A clear understanding of the implications of various cognitive impairments, along with a careful consideration of proposed clinical research methodology, is required. Assessment is complex; simply answering a certain number of factual questions about a protocol may not be an adequate assessment. A key factor in participants' decision- making is their appreciation of how the risks, benefits, and alternatives to participation in the study apply to them personally.

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schizophrenia may have fluctuating capacity. Researchers should be sensitive to the differing levels of capacity and use assessment methods tailored to the specific situation. Further, researchers should carefully consider the timing of assessment to avoid periods of heightened vulnerability when individuals may not be able to provide valid informed consent.

Both the IRB and clinical investigators must keep in mind that decision-making capacity may fluctuate, requiring ongoing assessment during the course of the research. The consent process should be ongoing and therefore the study should be explained again after enrollment. The IRB, at its discretion, may require an outside witness to observe the consent process.

Because no generally accepted criteria for determining competence to consent to research exists for persons whose mental status is uncertain or fluctuating, the role of the IRB in assessing the criteria proposed by the investigator is of major importance. The selection of an appropriate representative to give permission on behalf of those unable to consent for themselves must be accomplished without clear guidance from statutes, case law, or regulations. In cases of high risk studies, the IRB may also call on the primary care physician of individual subjects to comment on the subject’s ability to give consent to participate.

The determination of a participant's ability to understand the implications of the decision to participate in research is best made by the clinician/investigator. In most cases, the clinician/investigator is in the ideal position to evaluate the participant's ability to understand the implications of the research and whether the participant is making a rational decision to participate. Likewise, it is the clinician/investigator that makes a judgment of the participant's ability to understand and follow the protocol.

There is no universally accepted test or standard for making a determination of comprehension. This process should operate in research studies in much the same manner as the informed consent process in clinical treatment that does not involve research. However, protocols involving participants with the potential for developing impaired decision-making capacity during the course of the study must outline the steps a researcher should take when such change in capacity occurs.

Closely related to the determination of the ability to comprehend the nature of the study is the importance of ensuring that the participants' participation is completely voluntary. Some knowledge and assessment of the participant's competence is relevant to a determination of whether voluntary participation is evidenced by a written consent, or in the case of persons lacking legal capacity to consent, their assent. Research should not be conducted against the wishes of the participant, and making certain that the written documents are indeed a reflection of reality is the function of the individual researcher and the IRB.

There are many situations in which a participant should be encouraged to include the involvement of family members. However, the permission of another party will be required only when the participant is determined to lack the legal ability to provide his or her own informed consent. This would include minors (persons under the age of 18) and persons adjudicated incompetent. This also includes persons who are not capable of understanding the nature of their illness or the risks, benefits, and natural consequences of participation.

Definitions and Issues for Review when Studies Involve those with Diminished Capacity:

The IRB defines the legally authorized representative as a court appointed representative or an individual named as a health care proxy to make decisions for another individual about participation in research. This means the person who is possessed of the legal and rightful power to act for or on behalf of another.

The IRB will approve such research when:

1. The research holds out the prospect for direct benefit to the participant; the benefit is only available in the context of the research, and permission will be obtained through the legally authorized representative; or

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2. The research is of minimal risk, the research question cannot be answered using adults able to provide consent, permission will be obtained from the legally authorized representative, and when possible, assent will be obtained from the participant; or

3. The research is of more than minimal risk, the research question cannot be answered using adults able to consent, the research holds out a prospect of direct benefit to all participants, permission will be obtained from the legally authorized representative, and when possible, assent will be obtained from each participant.

Obtaining Assent from those with Diminished Capacity:

While reviewing studies that involve children, the IRB will assess the investigator’s plan for obtaining permission from legally authorized representatives as well as plans for obtaining assent from the participants.

In developing the assent, the investigator is obligated to incorporate any special accommodations necessary to assure that the subject population and or their authorized representatives comprehend the nature and purpose of the study. Useful techniques may include simplified consent documents, supplemental summary sheets, and formal Q&A sessions for the subject and legally authorized representative. Finally, the investigator should consider “waiting periods” after the initial discussion before the prospective participant actually enrolls.

15.4 Research Involving Prisoners

Generally, DF/HCC does not conduct research that plans to involve prisoners as participants. At times participants may unexpectedly become incarcerated. In such cases, investigators must contact OHRS as soon as they receive information that a current research participant has been incarcerated.

The PI will be asked to address the following: 1. Whether the participant is receiving any treatment as part of the research; 2. Whether all treatment can be provided as standard care; 3. Whether alternative treatments are available as standard care and would be acceptable substitutes for treatments available only in the context of the research.

If there is a reason for the participant to remain in the research, the research will be re-reviewed by the IRB with participation from a prisoner representative to affirm that it is appropriate for the incarcerated individual to remain as a participant in the research.

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Section 16 - Recruitment Procedures

The DFCI IRB is required to review:  The process to be used to solicit participation in the study  Advertisements/postings of any kind  Letters for prospective participants, regardless of the sender  Internet/database postings for which the opportunity to add additional descriptive information is not precluded by the data base system

IRB review of this material is to assure that: the language is appropriate for the audience; the information provided is true and clearly presented; and it does not promise or imply a certainty of cure or other benefit beyond what is contained in the protocol and the informed consent document.

The DFCI IRB is not required to review:  Communications intended to be seen or heard by health professionals only, such as "Dear Doctor" letters and Doctor-to-Doctor letters (even when soliciting for study participants)  News stories  Publicity intended for other audiences, such as financial page advertisements directed toward prospective investors  Listings of clinical trials on the internet ONLY when the system format limits the information provided to basic trial information, such as the title; purpose of the study; protocol summary; basic eligibility criteria; study site location(s); and how to contact the site for further information. [For example, the National Cancer Institute's Physician Data Query (PDQ), ClinicalTrials.gov, or the government- sponsored AIDS Clinical Trials Information Service (ACTIS)]

Any bonus payments to investigators as incentives for participant recruitment must be disclosed to the appropriate Conflict of Interest (COI) official and the IRB. All recruitment procedures must conform to the Partners’ Policy of Recruitment of Subjects which can be found on the Partners and OHRS websites.

Potential study participants may be identified through any of the following methods:

16.1 Private Medical Information

A common method of identifying potential trial subjects is to review medical records, clinical databases, and patient registries. This method allows members from the study team to review records and identify eligible individuals for a specific trial. However, the privacy and confidentiality of all individuals must be carefully protected. The privacy rules under the Health Insurance Portability and Accountability Act (HIPAA) as modified by HITECH and the Omnibus Rule, require this protection. The IRB must review and approve all such methods of obtaining private medical information prior to initiation.

16.2 Referring Physicians

Referrals from treating physicians can also be useful in identifying potential trial subjects. Treating physicians are most familiar with an individual’s medical status and can therefore be quite helpful in recommending a proposed trial as an alternative to his or her patient. For example, referring physicians who have been provided with general information about the trial may inform their patients that the trial is available and provide Version: March 2017

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the patients with contact information to learn more about the trial and whether they might be eligible. However, the referring physician cannot verify or check eligibility or obtain consent.

16.3 Advertisements

Advertisements (e.g., TV, Radio, posters, flyers) should be limited to the information necessary for potential trial subjects to make an informed decision. They should not make any claims regarding the safety and effectiveness of the investigational agent. Such representation would not only be misleading to participants but would also be a violation of the regulations concerning the promotion of investigational drugs 21 CFR 312.7(a) and of investigational devices 21 CFR 812.7(d).

Furthermore, advertisements should not promise “free medical treatment” when the intent is only to say that participants will not be charged for taking part in the investigation. Advertisements may state that participants will be paid but should not emphasize the payment by such means as larger or bold type.

Terms such as “new treatment,” “new medication,” or “new drug” should be excluded, and explanations of the test agent being investigational should be avoided. A phrase such as “receive new treatments” may lead trial participants to believe they will be receiving newly improved products of proven worth.

Generally, the FDA takes the position that any advertisement to recruit participants should be limited to the information the prospective participants need to determine their eligibility and interest. When appropriately worded, the following items may be included in advertisements (note that the FDA does not require inclusion of all of the listed items):

 Name and address of the clinical investigator and/or research facility  Condition being research and/or the purpose of the research  In summary form, the criteria that will be used to determine eligibility for the trial  A brief list of participation benefits, if any (e.g., a no-cost health examination)  The time or other commitment required of the participants and  The location of the research and the person or office to contact for further information

All advertising materials must be reviewed and approved by the IRB prior to distribution.

16.4 Recruitment Letters

Recruitment letters provide another means for informing potential study participants about ongoing or new research projects and inviting them to learn more about these trials. The following should be included in the letter:

1. A statement that a research trial is being conducted; 2. An explanation of the purpose of the research; 3. A brief description of what is involved in the research; 4. The expected duration of participation; 5. An “opt-out” or “opt-in”; a. Opt-out: Either a telephone number to call or a postcard to return if the participant is not interested. If neither is returned, the investigator may then attempt to contact the individual to determine whether the participant is interested in learning more about participating in the trial. Version: March 2017

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The “opt-out” option must be justified to the IRB due to the required effort of the potential participant. b. Opt-in: Either a telephone number to call or a postcard to return if the participant is interested in learning more about participating in the trial. In this case, the investigator may not contact participants who have not called or returned the postcard.

The study team must take special precautions to ensure that the letters are properly addressed to the correct individual and that the return address is generic (i.e. it doesn’t include the hospital or clinic name but only the street, city, state and zip code). Also, the return postcards should never contain information regarding a medical condition, medication, or diagnosis of those being contacted. The letter should be signed by both the PI and the treating clinician if possible, in keeping with the Partners’ recruitment policy.

Note: The DFCI IRB does not allow investigators to recruit their employees, students, or anyone working under them to be volunteers in their research trial. There is the appearance of conflict of interest as well as the appearance of coercion or undue influence. Depending on institutional policy, employees and students from other departments may be recruited to participate in such trials.

16.5 Scripts

A phone call, whether initiated by the research team or the potential participant, may be the first contact prospective study participants have with the research team. Calls are used as part of a recruitment process in order for people to obtain information about the study or determine basic eligibility for the study. The procedures followed must adequately protect the rights and welfare of the prospective participants.

In some cases personal and sensitive information is gathered about the individual. The IRB must have assurance that the information will be appropriately handled. A simple statement such as "confidentiality will be maintained" does not adequately inform the IRB of the procedures that will be used. In the proposal to the IRB, a description of what will happen to personal information if the caller ends the interview or hangs up unexpectedly is required.

16.6 Unacceptable Language and Suggested Alternatives

Unacceptable: “We are very excited to be able to offer...” Alternative Language: · “We are conducting a research study that may be of interest to you...” · “You may be interested in...” · “We hope to learn a great deal from this study...”

Unacceptable: “You may benefit from participation in...” Alternative Language: · “Although there may be no direct benefit to you, your participation in this study will help us learn...” · “It is unlikely that you will receive direct benefit from taking part in this study...” · “It is unknown whether or not participants in this study will receive any direct benefit...” Unacceptable: “You may qualify for...”

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Alternative Language: · “You may be eligible for...” · “The entry criteria for this study are...” · “This study is open to people with...” · “We are looking for people with...”

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Section 17 - Screening Potential Trial Participants

Once potential trial participants have been identified, a member from the study team may wish to establish contact, either by phone or in person, to determine initial eligibility for participation in the trial. The privacy and confidentiality of the individuals and all information collected regarding their medical history must be protected and maintained. Acceptable means of identifying and contacting potential trial participants are outlined in the section on Recruiting Trial Participants.

The use of screening tests to assess whether prospective subjects are appropriate candidates for inclusion in trials is an appropriate pre-entry activity. Although an investigator may discuss availability of trials and the possibility of entry into a trial with a prospective subject without first obtaining consent, informed consent must be obtained prior to initiation of any clinical procedures that are performed solely for the purpose of determining eligibility for research, including withdrawal from medication (washout). When washout is done in anticipation of or in preparation for the research, it is part of the research.

Procedures that are to be performed as part of the practice of medicine and which would be done whether trial entry was contemplated, such as for diagnosis or treatment of a disease or medical condition, may be performed and the results subsequently used for determining trial eligibility without first obtaining consent. On the other hand, informed consent must be obtained prior to initiation of any clinical screening procedure that is performed solely for the purpose of determining eligibility for research. When a doctor-patient relationship exists, prospective subjects may not realize that clinical tests performed solely for determining eligibility for research enrollment are not required for their medical care. Physician- investigators should take extra care to clarify with their patient-subjects why certain tests are being conducted. (Source: FDA Information Sheets)

A screening consent template on the OHRS website should be used with studies where a specific research test, such as genetic testing for a biomarker or the presence of a specific mutation, is required before enrolling on the clinical trial.

17.1 Appropriate Information to Gather

Only information pertaining to the specific inclusion/exclusion criteria for the trial should be obtained during the screening session. Information regarding the feasibility of the individual’s participation in the trial is also appropriate. For example, if the trial requires frequent visits to the clinic and the individual resides out-of-state, it may be appropriate to ask whether she would be willing to commit to the protocol requirements.

Information that does not specifically relate to the trial’s eligibility criteria should not be sought.

17.2 Screening Procedures

All screening activities (i.e., scripts, questionnaires, screening tools) are considered part of the subject selection and recruitment process and, therefore must be reviewed and approved by the IRB prior to initiation. Such procedures should be outlined in the protocol document or research application.

Telephone Screening

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Once a member of the study team has identified herself as such, she should immediately express the possible sensitive nature of the questions to be asked and the expected length of the conversation and then confirm that this is an appropriate time to conduct the screening interview.

Only upon deeming the participant eligible for enrollment and ascertaining the individual’s interest in enrolling should any contact or identifiable information (i.e., name, address, date of birth, social security number) be recorded. Until then, only the participant’s initials should be documented. Under HIPAA the historical medical information from identifiable participants obtained during a screening assessment constitutes “Protected Health Information (PHI)”. Collection of PHI requires researchers to provide participants with the institution’s privacy policy and also obtain a separate authorization to use and disclose the information. However, if only the participant’s initials are recorded during the screening, prior to establishing eligibility, the information is not considered PHI.

In-Person Screening

Participants may prefer to conduct the screening interview in person. The questionnaires, scripts, and checklists used for phone interviews are also appropriate for in-person interviews. As stated earlier, only information pertaining to the participant’s eligibility should be gathered. Administering eligibility tests and medical exams is considered trial activity and may not be conducted until after the participant has agreed to participate and has signed a consent form.

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Section 18 - Protocol Design

18.1 The Protocol Document

All DF/HCC research projects involving human participants must be written as protocols. The OHRS and Clinical Investigator Toolkit sections of the DF/HCC web site provide guidelines for writing minimal risk and greater than minimal risk protocols in the DF/HCC format. Cooperative group trials have their own required format and thus are exempt from the DF/HCC protocol format. Protocols written elsewhere, such as industry sponsored trials need not be placed in DF/HCC format.

The essential elements of the protocol are:

Synopsis of the Protocol  The objective(s) of the research protocol  Current knowledge and relevant literature  Rationale for the use of the selected study population  Statistical/qualitative methodology  Explicit inclusion/exclusion criteria  How the inclusion/exclusion criteria are assessed  Participants’ alternatives to participation in the trial  Consent process or request to waive consent

Risks to Participants  Risks (anticipated and potential)  Risks from trial article/research procedures (i.e., washout risks, placebo assignment)  Expected frequency, degree of severity, and reversibility  Possible late effects  Assessment procedures for the occurrence of adverse events  For trials with more than minimal risk, or FDA-regulated products/trials, plan for monitoring trial and data

Potential Benefits

 Potential direct or indirect benefits to the participant  Potential benefits to the group or class from which the participants are recruited  Potential benefits to society

Risk/Benefit/Alternative Assessments

 The risk/benefit ratio of participants’ participation, including careful consideration of alternative therapy, benefit to the class of patients, and benefits to society

Procedures  Duration of participants’ active participation  Follow-up after active participation ends  Number, duration, and nature of trial visits/encounters  Procedures to be performed solely for the purposes of the research

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18.2 Protocol Sections Sections of a protocol document will often include:  Title Page  Outline of current and previous version information  Table of Contents  Study Schema  Summary of the Study  Background and Significance  Statistical Considerations  Study Objectives and Endpoints  Enrollment and Registration Information  Eligibility Criteria  Pre-Therapy Evaluations  Treatment Plan  Expected Adverse Events, Dose Modifications and Un-blinding Information  Drug Information  Reporting of Adverse Events  Data Collection & Required Data Tables  Follow Up Monitoring of Study Participants  Long-Term Follow Up/Survival Data Collection  Submission of Collected Research Specimens; Ancillary Studies Information  References  Appendices

It is critical that the protocol document be kept as simple as possible and that only necessary requirements and tests be included in each trial. Once a protocol is activated, it must be followed as written (except for emergent safety reasons as described below). Auditors will monitor compliance with the protocol as it was written and approved by the IRB. The more complicated a protocol, the more difficult it is to follow. Consistency and accuracy are critical. Although amendments can correct issues with the protocol, these require increased effort from the investigator and time for appropriate review. Therefore, careful consideration of the trial design, including eligibility requirements, required data elements, and length of follow-up is essential.

Investigators may not improvise on the protocol plan (e.g. perform activities usually associated with standard of care or for subject convenience). A protocol must be implemented exactly as it is approved.

Many protocols include follow-up. It is important that the protocol and the consent identify the information and procedures that will be included in follow-up of the participant.

Any changes to the protocol must be first approved by the IRB, unless the safety of research subjects enrolled is at stake. If the change is designed to eliminate immediate hazard to subjects investigators are advised to inform OHRS of the situation and to make the necessary change(s) prior to IRB review and approval 45 CFR 46.103(b)(4) and 21 CFR 56.108(a)(4). OHRS must be formally advised of these changes (i.e. prompt submission of an amendment, unanticipated problem report or a major deviation/violation report). Depending on the situation, Investigators will be directed as to how to report the event to the IRB when they inform OHRS of the situation. Version: March 2017

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Section 19 - Informed Consent

19.1 Informed Consent Document

The regulations found at 45 CFR 46.116 state the following:

Except as provided elsewhere in this policy, no investigator may involve a human being as a subject in research covered by this policy unless the investigator has obtained the legally effective informed consent of the subject or the subject's legally authorized representative. An investigator shall seek such consent only under circumstances that provide the prospective subject or the representative sufficient opportunity to consider whether or not to participate and that minimize the possibility of coercion or undue influence. The information that is given to the subject or the representative shall be in language understandable to the subject or the representative. No informed consent, whether oral or written, may include any exculpatory language through which the subject or the representative is made to waive or appear to waive any of the subject's legal rights, or releases or appears to release the investigator, the sponsor, the institution or its agents from liability for negligence.

Informed consent is not merely obtaining a signature on a piece of paper. Rather, it is an involved process meant to:  Provide adequate information to allow an informed decision  Explain the nature and expectations of the research  Present the trial in a language that is clear and understandable  Answer questions raised by the participant  Provide enough time to allow for appropriate decision making  Explain the right to refuse participation

Per 45 CFR 46.116 (Department of Health and Human Services, DHHS) and 21 CFR Part 50 (FDA), basic elements of informed consent must include:  A statement that the trial involves research  An explanation of the purposes of the research  The expected duration of the participant’s participation in the research  A description of the procedures to be followed  Identification of any procedures that are experimental  A description of any foreseeable risks or discomforts to the participant  A description of any benefits to the participant or to others that may reasonably be expected from the research  Disclosure of appropriate alternative procedures or courses of treatment, if any, that might be advantageous to the participant  A statement describing the extent, if any, to which confidentiality of records identifying the participant will be maintained, and if applicable, a statement that the FDA may inspect the records  For research involving more than minimal risk, an explanation as to whether or not any compensation is available if injury occurs; whether or not any medical treatment is available if injury occurs, and if so, what they consist of; and whether or not further information can be obtained  An explanation of whom to contact for answers to questions about the research, research participants’ rights, and whom to contact in the event of a research-related injury to the participant  A statement that participation is voluntary, that both refusal to participate and discontinuing participation at any time can be done without penalty or loss of benefits to which the participant is otherwise entitled Version: March 2017

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Additional elements of informed consent are generally required by the DFCI IRB and include:  A statement that a particular treatment or procedure may involve risks to the participant that are unforeseeable  The anticipated circumstances under which the participant’s participation may be terminated by the investigator without regard to the participant’s consent  Any additional costs to the participant that may result from participation in the research  The consequence of a participant’s decision to withdraw from the research and procedures for orderly termination of participation by the participant  A statement that significant new findings developed during the course of the research, which may relate to the participant’s willingness to continue, will be provided to the participant  The approximate number of participants involved in the trial  The trial treatment(s) and the probability of random assignment to a placebo or to treatment  The IRB may require that information (in addition to that required by the regulations) be given to research participants when by its judgment the information would meaningfully add to the protection of the rights and welfare of participants

The consent document should be clear and descriptive enough to stand alone in describing the proposed research.

19.2 Standardized Consent Form Template

All new protocols submitted to the IRB are required to use the most current consent form template. The template is designed to provide greater understanding and improve potential subjects’ decision-making for participation in a clinical trial. The informed consent template will aid investigators in writing informed consent documents and will assist the IRB in the review of such documents. Investigators should familiarize themselves with the OHRS guidance regarding informed consent on the OHRS website.

The DFCI IRB requires the use of “Participants” in the consent form document as opposed to the regulatory term “subjects”. Study teams are also expected to use the DFCI IRB approved language to draft the risks incorporated in the consent form for submission to the IRB.

The template, guidelines, IRB approved language databases, and instructions can be found on the OHRS website.

19.3 Incentives and Remuneration for Study Participants

Each year, thousands of individuals are paid for participating in biomedical and behavioral research funded either by federal departments and agencies or private institutions. Although payments are usually monetary, both patients and normal healthy volunteers may be offered other rewards in lieu of or in addition to money. The amount and schedule of all payments should be presented to the IRB at the time of initial review. Taking into consideration the population to be recruited, and the medical, employment, and educational status, financial, emotional and community resources, as applicable, the IRB must determine whether the rewards offered for participation in research constitute undue inducement.

Any credit for payment should accrue as the study progresses and should not be contingent upon the participant completing the entire study. Payment to participants who withdraw from the study may be made at the time they would have completed the study (or completed a phase of the study) had they not withdrawn. For example, in a study lasting only a few days, an IRB may find it permissible to allow a single payment date at the end of the study, even to participants who withdrew before that date. If this policy appears coercive

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within the context of a particular study, arrangements should be made to provide payment on a different schedule.

While the entire payment should not be contingent upon completion of the entire study, payment of a small proportion as an incentive for completion of the study is acceptable. The IRB should determine that the amount paid as a bonus for completion is reasonable and not so large as to unduly induce participants to stay in the study when they would otherwise have withdrawn.

All information concerning payment, including the amount and schedule of payment(s), should be set forth in the informed consent document.

We recommend the following as guidance to investigators and the IRB: 1. When offered, incentives should generally not exceed $20-$25 per hour or $200-$250 per day, whichever is less; 2. The amount should be calculated based on the incremental time that study participants spend for research purposes; 3. Incentives may be offered to patient-participants as well as to healthy volunteers; 4. Incentives must be described in any advertisements and in the consent form; 5. In addition to the incentives described above, remuneration for parking, meals, and other expenses incurred due to participation in a trial is appropriate for all study participants.

19.4 Assent and Children in Research

Assent is “an agreement by an individual not competent to give legally valid informed consent to participate in research.” Children, adolescents and people with mentally diminished capacity fall into this category and therefore, may be asked for their assent to participate in research.

The assent process seeks to obtain an element of understanding and cooperation on behalf of the child. It also attempts to provide the child with a sense of inclusion, respect, and dignity in terms of his or her decision to take part in research.

While reviewing research that includes children, the IRB must determine that adequate provisions for soliciting assent are in place. Factors such as age, maturity, and the psychological states of the children play roles in the IRB determining whether the potential subjects are capable of understanding the nature of their participation in the research. The DFCI IRB requires that assent be obtained from children ages 10 to 17 under normal circumstances.

The IRB will assess the investigator’s plan for obtaining permission from parents/guardians as well as plans for obtaining assent from the children.

In cases where the studies are of minimal risk to the child, the permission of one parent may be sufficient. In cases where the research presents more than minimal risk to the child but there is the prospect for direct benefit, the IRB may also find it sufficient to ask for permission from one parent.

When the IRB reviews a study that involves more than minimal risk for the child and does not hold out the prospect for direct benefit but does offer an opportunity to learn more about the disease under study, the IRB will require the permission of both parents when both are reasonably available.

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19.5 IRB Waiver of Informed Consent 45 CFR 46.116(d)

An IRB may approve a consent procedure that does not include, or that alters, some or all of the elements of informed consent set forth in this section, or waive the requirements to obtain informed consent provided the IRB finds and documents that: 1. The research involves no more than minimal risk to the participants; 2. The waiver or alteration will not adversely affect the rights and welfare of the participants; 3. The research could not practicably be carried out without the waiver or alteration; 4. Whenever appropriate, the participants will be provided with additional pertinent information after participation; 5. If personal identifiable information will be collected, the following must be addressed: a. The plan in place to protect identifiers from improper use or disclosure; b. When and how identifying information will be destroyed; c. Why the research could not be practicably conducted without access to/use of this identifiable information.

NOTE: The FDA regulations do not permit a waiver of informed consent except in very limited circumstances such as in emergency situations (see 21 CFR 50.23).

19.6 IRB Waiver of Documentation of Informed Consent 45 CFR 46.117(C)

An IRB may waive the requirement for the investigator to obtain a signed consent form for some or all participants if it finds either:

1. The only record linking the participant and the research would be the consent document and the principal risk would be potential harm resulting from a breach of confidentiality. Each participant will be asked whether they want documentation linking the participant with the research, and the participant’s wishes will govern; or 2. The research presents no more than minimal risk of harm to participants and involves no procedures for which written consent is normally required outside of the research context.

In cases in which the documentation requirement is waived, the IRB may require the investigator to provide participants with a written statement regarding the research.

NOTE: In accordance with 21 CRF 56.109, the FDA regulations permit a waiver of documentation of informed consent for research involving no more than minimal risk of harm to participants and involves no procedures for which written consent is normally required outside of the research context.

19.7 Guidelines for Obtaining Consent

Clinicians and investigators have an obligation to obtain the informed consent of the participant (or the appropriate surrogate) before enrolling him or her in a clinical trial. Informed consent to clinical trials share much in common with informed consent to ordinary clinical care, including such key elements, as the procedures the participants will undergo, the risks of those procedures, the potential benefits of undergoing the procedures, and the alternatives to the proposed course of action.

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General Guidelines When obtaining informed consent to research, the clinician/investigator should emphasize the ways in which clinical trials differ from ordinary clinical care:  Clearly identify one or more non-research alternatives to the clinical trial (including palliative care, where appropriate)  Clearly identify the incremental risks and benefits of the clinical trial, compared with the non- research alternative(s).  Clearly identify the uncertainty associated with the experimental treatment under investigation.

Timing of Consent Evidence shows that participants who have time to consider their decisions and review the consent form are better informed than those who do not. Therefore, unless there is a strong reason to obtain consent at the first conference (i.e., medical urgency), clinicians/investigators are strongly encouraged to give participants at least 24 hours to consider their decision before obtaining signed consent.

Participants in the Consent Process Evidence also shows that the participation of a professional third party in the consent process is associated with improved understanding. Whenever possible, clinicians/investigators are urged to include a nurse, psychosocial clinician, or other member of the study team in consent conferences.

Reading the Consent Form Clinicians/investigators should strongly encourage potential participants to read the consent form carefully before deciding about participation.

19.8 DFCI IRB Policy and Guidance Documents Available on the Consent Process: http://www.dfhcc.harvard.edu/clinical-research-support/office-for-human-research-studies-ohrs/information- sheets/

 Requirements for Informed Consent  Consent Form for Continued Participating for Young Adults Who Have Reached Aged 18  Instructions for Obtaining & Documenting Informed Consent of Non-English Speaking Subjects  Short Form Translational Procedure  Withdrawal of Consent to Continue in Research  Procedures for Monitoring Consent Process

During its review, the IRB may find protocols that require monitoring or auditing of the consent process in order to assure that participants are adequately and appropriately provided information related to their ability to make an informed decision about participation in a research study. This guidance document provides researchers with information about monitoring the consenting process.

 Legally Authorized Representatives  Use of Informed Consent Documents Posted to OncPro  OHRS Standard Language Database  Pregnant Partner Consent and Data Collection  Discussing Enrollment in a Clinical or Non-Clinical Trial with Prospective Participants

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Section 20 - Protocol Submission, Review and Activation

DF/HCC requires a detailed review of all trials. This section describes the protocol review process and briefly discusses the roles of the offices and committees involved in the reviews.

20.1 Required Review

DF/HCC Scientific Review is required for:  Oncology research projects that involve human participants and that are conducted by students, faculty members, or staff of the following institutions: . BIDMC . BCH . BWH . DFCI . MGH . Satellite Sites . Network Affiliates

DFCI IRB review is required for:  All research projects that involve human participants and that are conducted by students, faculty members, or Dana-Farber Cancer Institute staff;  Oncology research projects that involve human participants and that are conducted by students, faculty members, or staff of the following institutions: . BIDMC . BCH . BWH . MGH . Satellite Sites . Network Affiliates (using DFCI as IRB of record)

The DFCI Office for Human Research Studies (OHRS) is the office that manages the DF/HCC SRC and DFCI IRB Review Processes.

20.2 Submitting a Trial for Review

All submissions are sent electronically through OHRS Submit. The instructions and requirements are described fully on the OHRS website.

The review process begins when the OHRS receives the complete submission package.

Incomplete submissions will not be routed for review until the submission is complete. Therefore, investigators should review the instructions on the application forms for each type of submission. Submission forms are available on the OHRS website.

20.3 Elements of a New IRB Submission

Please refer to the OHRS Information Sheet titled: New Protocol Submission Requirement Chart.

 Endorsement Form - The Disease or Discipline-based Program Leader is a DF/HCC position that oversees the functions of a specific disease or discipline-based program. The Program Leader or

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designee is required to sign off on all new protocol submissions via the endorsement form. This signature implies that the leader has reviewed the protocol with the appropriate Program members and the decision has been made that the protocol fits into the priorities of the overall research plan for the program.

 Front Sheet

 New Project Application Form - The application form must be completely filled out and include information about the Data and Safety Monitoring Plan:

Data and Safety Monitoring Plan (DSMP) - A data and safety monitoring plan may incorporate many different methods of monitoring. The DF/HCC Data and Safety Monitoring Plan (http://www.dfhcc.harvard.edu/clinical-research-support/quality-assurance-office-for-clinical-trials-- qact/forms-policies-and-manuals) describes how we monitor protocols. A Data Safety Monitoring Board (DSMB) must review all phase III protocols. DF/HCC has a central DSMB that must be used for all PI- initiated protocols. The DF/HCC Data Safety Monitoring Committee (DSMC) reviews High Risk, PI-Initiated Phase I and II trials.

High risk is defined as any of the following: the first time in humans, the first time in children, gene transfer, or multi-center. These DF/HCC committees may also review other protocols that do not have an outside committee reviewing them.

 Statement of Principal Investigator Form, Statement of Co-Investigator Forms and Study Specific Research Team Update Form

 Conflicts of Interest (COI) Disclosures- Statement of Principal Investigator and Statement of Investigator - The IRB requires that investigators submit conflict of interest information on a trial-by- trial basis by completing the Statement of Principal Investigator, Statement of Investigator, and Outside Interest Log Forms This information is requested on each new protocol application form and asks that investigators indicate any conflicts of interest that they may have. In situations where an investigator may have potential financial conflicts of interest, the IRB may ask the investigator to explain how the potential conflict of interest will be minimized or resolved and may require disclosure of conflicts of interest in consent forms. The IRB may also request input from the Conflict of Interest (COI) Officials for managing individual conflicts of interest.

 Priority List - The protocol priority lists outline available protocols for participants with a given disease. The listing includes pending, active, and closed protocols. They are available for distinct disease programs (e.g., breast) and are broken down by site and extent of disease. Each program is responsible for prioritizing protocols within their specific area. Protocols must be prioritized within the appropriate category prior to submission to the IRB.

Protocols are prioritized to ensure the efficient completion of trials. It is designed to minimize competing protocols and to effectively utilize the resources that manage the clinical trial process, including central core facilities, participants, and staff.

Priority lists for adult and pediatric protocols, both clinical and non-clinical, are available via OncPro.

 Protocol Document - A detailed research protocol is required for IRB review of your research. Guidelines for writing greater than minimal risk protocols and behavioral and social protocols are available on the OHRS website and in the DF/HCC Clinical Investigator Toolkit.

 Investigator Brochure (IB), Device Specifications, and Package Inserts - The IRB is required to examine the investigator brochure (known as IB) and/or device manual in order to adequately assess the risk/benefit ratio for participants participating in the research. When approved drugs or devices are Version: March 2017

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being used, a copy of the package insert should be submitted with the application materials. During the conduct of the trial, all updates to these manuals must be sent to the IRB and the Research Pharmacy.

 Research Nursing/Pharmacy Protocol Screening Form

 Correspondence with FDA or OBA - Studies involving the use of any investigational or unlicensed test article must include copies of all relevant correspondence between the sponsor and the FDA. The IRB will not grant IRB approval without the IND/IDE approval (or documentation of exemption).

Relevant correspondence would include: o Documentation of the FDA assigned IND/IDE number for the proposed research. o Confirmation of an FDA granted exemption

 Study Diary

 Recruitment Material (Advertisements, Posters, Flyers, Press Releases, etc.) The IRB reviews any advertisements, flyers, and Internet postings for participant recruitment, as well as correspondence to participants prior to its use. NCI’s Physician Data Query (PDQ) postings do not need to be submitted for IRB review and approval.

All recruitment materials must be submitted with the initial application. Advertisements, press releases, etc. may qualify for expedited review.

 Informed Consent Document - The required template and IRB-required and suggested language for consent forms are available on the OHRS website.

 Sponsor Sample Consent Document

 Interview Scripts, Surveys and Questionnaires - The IRB reviews all research instruments such as surveys or questionnaires. All instruments must be submitted with the initial project application.

 Grant Application(s) - Research that will or may be funded by a grant must include a copy of the grant for IRB review. To perform a complete review, the IRB is required to examine the grant proposal. Investigators need not include the funding section or the breakdown of dispersal of funds unless requested by the IRB.

20.4 Other Required Documents

Prior to trial activation, there are several documents that may be required by trial sponsors. These are outlined below.

 FDA Form 1572 This form is a component of an IND application. It provides the name and address of the institution where the clinical investigation will be conducted, the names of the PI and all other sub-investigators, and other pertinent trial information.

The FDA Form 1572 outlines the duties and obligations of investigators. It is imperative that all investigators read it. The overall investigator within the DF/HCC is the only one required to sign the 1572, committing to all the rules and regulations set by the FDA for conducting clinical trials. The site PI should not sign in addition. Curriculum vitae (CV) are required for the PI and for all other investigators as evidence that they are “qualified as an expert in the clinical use of the drug under investigation.” The completed form is submitted to the sponsor, who then incorporates the information into an IND application.

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For trials sponsored by the NCI, the ODQ will contact investigators once a year for updated information for each NCI-specific 1572. These 1572s must be submitted to NCI by August 1 of each year. Investigators must also provide to NCI an updated, signed, and dated CV as a part of this annual investigator registration process.

 Letter of Assurance from the IRB Many pharmaceutical sponsors will request a roster of the IRB members. The OHRS does not provide this roster. Instead, the OHRS provides a letter stating that the Institute is in compliance with all Massachusetts, HHS, and FDA regulations governing research on human participants. This letter also provides an Assurance Project Number on file with the federal government through the federal Office for Human Research Protections (OHRP). This “sponsor” letter is available on the OHRS website.

 Laboratory Normal Value and Letter of Certification Sponsors require evidence that the Clinical Laboratory Improvement Amendments (CLIA) certifies every laboratory monitoring the health of study participants. The laboratory values are used to assess toxicity and changes in laboratory values while the participant is enrolled in the trial. At DF/HCC, this information can be obtained from the various administrative directors of laboratories offices or the DF/HCC Clinical Research Unit website under “Regulatory Documents.” The Certificate of Pathology (CAP) for DF/HCC institutions is also included in the CLIA certificate. When laboratories outside the DF/HCC are used, the PI or the PI’s designee must contact them as the same information must be obtained and submitted to the trial sponsor. Laboratories used to process research samples only, who not to diagnose or treat patients, are not required to be CLIA-certified.

 Clinical Trials Agreement There is a legal contract between DF/HCC and the pharmaceutical sponsor. The clinical trial agreement is developed by research administration with input from DF/PCC, BIDMC, and BCH legal staff. The agreement includes the budget for the trial. The administrator from each division will assist investigators with actual budgets. Confidential clinical trials agreements are the property of the Institute and the investigator and will not be kept with the investigator’s trial binder.

 IRB-approved Informed Consent Pharmaceutical sponsors require receipt of the IRB-approved consent form prior to enrollment of the first participant. The OHRS recommends that consent documents be sent to the sponsor after IRB approval but prior to trial activation. Any changes requested by the sponsor must be reviewed and approved by the IRB. The study team must maintain copies of the approved consent documents in their trial files.

 Investigator Financial Disclosure Form All individuals listed on the 1572 are required by the pharmaceutical company sponsoring the trial to complete an investigator financial disclosure form. The form seeks to identify any significant equity, proprietary, or financial interest those participating in the trial may have in the company.

20.5 The Review Committees

Scientific Review Committee (SRC) As an NCI-designated comprehensive cancer center, DF/HCC is required to conduct a review of scientific merit for each research trial it reviews. To comply with the NCI requirement, and to assist the IRB panels in their review, the SRC focuses on scientific merit, scientific priorities, and the scientific progress of the clinical research protocols of the cancer center. There are three adult SRCs, one pediatric SRC and one SRC that reviews both adult and pediatric non-clinical research.

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The voting members of the SRC include the scientific chair, physicians, and biostatisticians. Additionally representatives from ODQ, pharmacy, and nursing departments provide input for SRC consideration.

Two physicians are assigned as the lead reviewers on each protocol. The primary and secondary reviewers are responsible for the thorough review of each protocol. These reviewers take the lead in the discussion of assigned projects. The entire SRC reviews and discusses all new protocols. Reviewer assignments are made by the OHRS.

All SRC deferrals must be sent back to the full committee for re-review. Protocols are not sent to the IRB until the determination has been made that the investigator has adequately responded to all conditions identified by the SRC.

Pediatric Scientific Review Committee (PSRC) The PSRC reviews all greater than minimal risk trials involving pediatric patients and ensures that the protocol is of appropriate scientific and therapeutic merit and is in accordance with the mission of the DFCI. All investigators from the department of pediatric oncology at DFCI must submit protocols to the PSRC for review and approval.

The committee chairperson appoints committee membership. Voting membership includes a representative from the major disciplines and includes physicians and biostatisticians. Additionally representatives from ODQ, pharmacy, and nursing departments also attend to provide input for PSRC consideration.

Institutional Review Board (IRB) Review Committees DF/HCC has seven fully functioning and federally registered IRB panels. Each one is made up of at least five members. At least two members are licensed physicians, one a non-scientist, and one a member who is not otherwise affiliated with the Institute.

While any IRB panel may review any protocol in any stage of the review and approval process, including amendments and deviations, the IRB panels generally review the following types of research:  IRB Panel A: New Clinical Trials  IRB Panel B: New Clinical Trials  IRB Panel C: Ongoing Clinical Trials  IRB Panel D: New and Ongoing Non-Clinical Research Studies  IRB Panel E: New and Ongoing Research that require immediate IRB action  IRB Panel F: Ongoing Clinical Trials  IRB Panel G: New and Ongoing Pediatric Clinical Trials

Please refer to the OHRS Information Sheet titled: Overview of the Operations of the DFCI Institutional Review Boards for more information.

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20.6 Description of Departmental Reviewers The following departments play a crucial role in the review of new and ongoing research. REVIEWER PURPOSE

Considers the availability and dispensing issues Pharmacy Department relative to the drug proposed for the trial and the accuracy of the protocol relating to pharmacy issues.

Reviews the clarity of the treatment plans and Nursing Department considers how the trial will affect staffing and training.

Office of Data Quality (ODQ) Considers the proper registration process for the trial and verifies that the document includes the essential elements for managing the trial. The ODQ also considers future forms development for computer entry.

Research Administration, Including Considers the protocol from a contractual Legal Consultation perspective; this includes negotiating with pharmaceutical companies and getting grants and funding sources. This process also includes a review of the study documents from a legal standpoint.

Office for Human Research Studies Conducts a pre-review of new project (OHRS) application submissions and the informed consent document.

20.7 Review and Approval of Other DF/HCC Departments/Committees

Institution Specific Departments/Committees with research review responsibilities include, but are not limited to:  Biomedical Engineering  Biosafety Officers and/or DFCI Institutional Biosafety Committee (IBC) and Harvard Committee on Microbiological Safety (COMS)  Radiation Safety Officers and/or Radiation Safety Committees (Rad Safety)  Cell Manipulation Core Facility (CMCF)  Tumor Imaging Metrics Core (TIMC)  Clinical Research Lab (CRL)

 Pathology Department  Clinical Trials Billing Department (CT Billing)  Grants office

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The OHRS activation team assists in the coordination of review with these departments and/or committees. Investigators will be informed of other review requirements upon receipt of the review from the SRC or PSRC. Studies conducted at MGH, regardless of which DF/HCC site is the lead, may require review by the MGH Pathology department, IBC and Radiation Safety Committee. These reviews are coordinated by the MGH Cancer Center Protocol Office and do not require a separate submission by the research team.

No project may be activated until all relevant committees have granted approval.

20.8 Notification of Committee Determinations and Departmental Reviews

OHRS will communicate the results of a review to the investigator and designated member(s) of the study team via email. Investigators are asked to respond to any conditions according to the timelines that will be communicated within the specific OHRS communication.

In cases where the IRB concerns are related to subject safety on an active trial, investigators may be expected to respond in a much shorter time frame. Any such expectations will be communicated in the email to the investigator and study team.

20.9 SRC and IRB Review Outcomes

The review committees may make one of the following determinations as a result of their review of research submitted for initial review, continuing review or any amendments to the research:

1. Approve: The protocol and accompanying documents are approved as submitted. Final approval will commence on the day the trial is approved by an action of the convened SRC/IRB or by the review of an individual designated to review submissions on an expedited basis.

During initial review, participants may not be recruited into the trial until final approval has been issued, administrative requirements are satisfied, and the protocol has been activated. Protocol revisions may not be initiated until final approval has been issued.

The conditions for continued approval and the time frame (if any) within which they must be met, will be stated in the approval letter. If the conditions are not met, approval may be withdrawn by OHRS.

2. Require Modifications (Conditional Approval): A vote of conditional approval is granted only when the committee finds that the required revisions are minor and need only to be incorporated into the protocol and/or consent document or if the required changes or information requested meet the criteria for expedited review. For example, this might be adding appropriate study staff, editing the consent form for clarity (but does not include adding information about risks to participants or about costs to participants) or requests for consistency between the protocol and other study documents.

A member of the IRB confirms responses to conditional approvals.

Any uncertainty or question about the investigator's response will be referred to the full committee for additional review.

3. Defer: Protocols are deferred when significant questions are raised during the review requiring its reconsideration after additional information is received from the investigator and/or sponsor. The investigator will be informed in writing of the required changes and requested information and must provide the IRB with the changes or information, or an explanation of why these changes are not necessary.

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4. Disapprove: A protocol may be disapproved where it fails to meet one or more of the criteria used by the IRB for approval of research. The investigator will be given a detailed communication describing the issues related to this disapproval. The investigator is allowed to respond to the IRB in person or in writing regarding this decision.

Disapproval or deferral cannot be given through the expedited review mechanism and may only be given by majority vote at a convened meeting of the IRB. If the IRB disapproves a trial, no other review body or person may grant approval.

5. Table: The IRB may table a review due to inadequate time or members present to conduct a thorough review. In this case, the investigator will be notified and the review will be rescheduled for another meeting.

20.10 Response to Committee Requests

The SRC and IRB require a response from investigators, in a point-by-point manner, preferably as soon as possible but no later than the time requirements set out in the communication.

Any conditions required by a review committee must be met as described in the decision memo. Disagreements with a decision or specific requirements should be documented and explained in the response. Investigators have the right to discuss committee decisions of disapproval directly with the committee. The IRB, however, retains the final authority for approval or disapproval of proposed human subject research.

20.11 Claim of Exemption

The DFCI IRB and DF/HCC require that investigators submit studies for confirmation of Exemption from IRB review pursuant to the regulations found at 45 CFR 46.101(b) and 21 CFR 56. 104.

Investigators are required to submit documentation on the “Request for Exemption or Determination That Activity Is Not Human Subject Research” form, which is available on the OHRS website. This allows a pre- submission consultation with the investigator. The DFCI IRB will consider the following types of research exempt from IRB review. Exemptions will not be granted to the following types of research when the study population includes prisoners.

Classifications of Exemption

1. Research conducted in established or commonly accepted educational settings, involving normal educational practices. This includes research on regular and special education instructional strategies, research on the effectiveness of or the comparison among instructional techniques, curricula, or classroom management methods.

This does not apply to research that is regulated by the FDA.

2. Research involving the use of educational tests (cognitive, diagnostic, aptitude, achievement), survey procedures, interview procedures or observation of public behavior, unless: a. Information obtained is recorded in such a manner that human participants can be identified, directly or through identifiers linked to the participants; and b. Any disclosure of the human participants' responses outside the research could reasonably place the participants at risk of criminal or civil liability or be damaging to the participants' financial standing, employability, or reputation.

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This does not apply to research that is regulated by the FDA.

3. Research involving the use of educational tests (cognitive, diagnostic, aptitude, achievement), survey procedures, interview procedures, or observation of public behavior that is not exempt, if: a. The participants are elected or appointed public officials or candidates for public office; or b. Federal statute(s) require(s) without exception that the confidentiality of the personally identifiable information will be maintained throughout the research and thereafter.

This exemption does not apply to children (anyone less than 18 years of age), except for research involving observation of public behavior when the investigator(s) do not participate in the activities being observed.

This does not apply to research that is regulated by the FDA.

4. Research involving the collection or study of existing data, documents, records, pathological specimens, or diagnostic specimens, if these sources are publicly available or if the information is recorded by the investigator in such a manner that participants cannot be identified, directly or through identifiers linked to the participants.

The IRB defines subjects who cannot be identified, directly or through identifiers linked to the participants’ as cases when the investigator has documented that she cannot and will not have access to the sources of these data or specimens then they are anonymous to the investigator. This attestation will be collected from investigators. Such materials must already exist at the time the research is proposed.

This does not apply to research that is regulated by the FDA

5. Research and demonstration projects which are conducted by or subject to the approval of Department or Agency heads, and which are designed to study, evaluate, or otherwise examine: a. Public benefit or service programs; b. Procedures for obtaining benefits or services under those programs; c. Possible changes in or alternatives to those programs or procedures; or d. Possible changes in methods or levels of payment for benefits or services under those programs.

This does not apply to research that is regulated by the FDA.

This exemption is for projects conducted by or subject to the approval of federal agencies. In order to meet the criteria for exemption under “public benefit” exemption criteria, the following criteria (see 48 FR 9266-9270) must be satisfied. The research or demonstration project must be conducted pursuant to specific federal statutory authority; there must be no statutory requirement that the project be reviewed by the IRB; the project must not involve significant physical invasions or intrusions upon the privacy of participants. This category will only be invoked when in the opinion of OHRP it is appropriate.

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the level and for a use found to be safe, or agricultural chemical or environmental contaminant at or below the level found to be safe, by the Food and Drug Administration or approved by the Environmental Protection Agency or the Food Safety and Inspection Service of the U.S. Department of Agriculture.

The following procedure is followed:

1. The investigator will submit the “Request for Exemption or Determination That Activity Is Not Human Subject Research” form, copies of grants, and proposals for funding and all other supporting documents, for review by an IRB member. 2. Once exemption has been determined, the investigator will receive an exemption letter explaining why the study meets the criteria for exemption and the related criteria from the regulations will be cited. Studies deemed exempt do not require continuing review. However, any changes to the research which may change the status from exempt to expeditable, for example, must be communicated by the investigator to the IRB via an amendment submitted through OHRS submit.

20.13 Protocol Activation and Distribution

OHRS coordinates the activation of IRB-approved research at each of the DF/HCC institutions as a separate function. Activation departments from the participating institutions which are affected or involved in the research are contacted to ensure that essential resources are available and that additional committee review (i.e., by Radiation Safety Committee, BioSafety Committee, etc.) has been completed when applicable.

Departments such as Pharmacy, Nursing, Radiation Safety, Clinical Research Lab, Pathology, Biomedical Engineering and BioSafety are contacted to ensure that the appropriate resources are available to protect research participants. These resources include, but are not limited to the availability of staffing and personnel, facilities and equipment.

In addition to the departments listed above, protocols are also routed to Research Administration (Grants and Contracts offices) at each of the institutions participating in the research to confirm that funding is available and contracts have been signed, etc.

After a protocol is approved and all activation requirements have been met, the PI will receive a memo indicating that the trial has been activated. The date of activation is the date when the investigator may begin to accrue subjects and actually start the research. Overall Principal Investigators are responsible for maintaining accurate records on the number of subjects enrolled in their trials regardless of whether registration is managed by the ODQ. Study enrollment cannot exceed the IRB approved accrual goal without IRB approval.

Once a trial has been activated, a full copy of the protocol document, consent form, eligibility checklist, and priority list will be available online via OncPro. Only the online version of the protocol and consent form may be used to ensure that the most updated and accurate information is used.

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Section 21 - Continuing Reviews In addition to reviewing all new protocols, the IRB also reviews the goals, accrual, and status of each ongoing protocol at least once a year. The IRB also reviews the consent forms for each active protocol.

The PI or designee must complete the “Continuing Review” form and submit it to the OHRS. This form includes such information as current accrual data, reasons for participant withdrawals, trial status and objectives, treatment description, summaries of toxicities and adverse reactions, any results obtained thus far, and any new information since the last IRB review including premature completion of a study. Depending on the type and status of the trial, the continuing review may qualify for an expedited review.

If no further research continues and data are is no longer being collected or analyzed on a trial, the PI must notify the OHRS that the trial is complete and must fill out and submit a final “Continuing Review” form covering the period between the previous review and the date the trial was completed. Once a trial is complete, no further research can take place.

As a courtesy to investigators, the OHRS sends a reminder memo to the PI and designated trial staff 90 days prior to IRB approval expiration. The OHRS requests submission of the continuing review form at least 60 days prior to the studies expiration date.

If a continuing review form is not received and IRB approval expires, the protocol will be placed on hold and a memo will be sent to the PI. Participant enrollment, treatment of participants considered on trial, and data collection/analysis must immediately cease.

The PI may submit a “Request to Continue Research Interventions” form to the IRB to request continued treatment of participants currently enrolled. These requests are considered on a case-by-case basis.

OHRS may report to the FDA, OHRP, and sponsors any reports of expired studies if they are determined the IRB to meet the definition of serious or continuing non-compliance. OHRS may also refuse to accept any new protocol submissions if a PI has two or more expired studies due to non-submission of a continuing review and/or study completion report.

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Section 22 - Changes to Previously Approved Research (Amendments)

22.1 Overview

Once a study has been IRB approved (and activated), the associated study documents (submission forms, protocol document, consent forms, alert page, front sheet, study diaries, recruitment materials, questionnaires, etc.) dictate how the study will be conducted. Changes in previously approved research, including changes to informed consent documents during the period for which IRB approval has already been given, may not be initiated without IRB review and approval except when necessary to eliminate apparent immediate hazards to the participant (45 CFR 46.103(b)(4)(iii) and 21 CFR 56.108(a) (3)-(4)). When applicable, activation requirements must also be met prior to the amendment being implemented.

Proposed amendments must be sent to the OHRS electronically via OHRS submit for review by the IRB. Minor changes to previously approved research may qualify for an expedited IRB review (review carried out by the IRB chairperson or by one or more experienced reviewers designated by the chairperson from among the members of the IRB). In reviewing the proposed amendment, the reviewers may exercise all of the authority of the IRB except that the reviewers may not disapprove the proposed changes. The proposed amendment can only be disapproved after review by the convened IRB. If a proposed amendment is not eligible for expedited IRB review procedures it will be routed directly to the convened IRB for their review. If there are significant scientific changes proposed P/SRC review may be required prior to IRB review. If the scientific changes proposed are minimal a biostatistician review may be requested prior to IRB review.

After IRB review, the study team will be contacted as to the outcome of the review. The possible review outcomes described earlier in section 20.9 “Review Outcomes” of this guide are also applicable to the review of amendments. If a response is required to the IRB conditions (and P/SRC if applicable), the study team is expected to provide a point-by-point response as soon as possible after the review outcome is disseminated to the study team.

Once any conditions are satisfied, the study team will be notified of the IRB approval by the OHRS Online Communications Team. If there are no activation requirements, the study team will receive an approval/activation memo and the revised study documents will be posted on OncPro for use by the study team. If the amendment is only IRB approved, and activation requirements must be met, the study team will receive only an IRB approval memo and the amendment will be routed for activation. Activation sign- offs for amendments are similar to the sign- offs required for new protocol submissions and are further described in section 20.7 “Review and Approval of Other DF/HCC Departments/Committees” of this guide. Once all activation requirements have been met, the amendment will be activated and the OHRS Online Communication Team will notify the study team of the amendment’s activation and post the revised documents on OncPro. At the time of approval/activation amendment changes are considered implemented and the study team may conduct the research using the revised study documents.

22.2 Types of Amendment Submissions

General Amendments

General amendments (including CTEP amendments, Dose Escalation Amendments and Updated Investigational Brochures) may include one or more of the following changes to the previously approved research and are submitted using the Amendment form: . Increased Risk to Participants: New Risk is Identified; Changes made as a result of an updated Investigational Brochure, Adverse Event or IND/IDE Safety Report necessitate changes to the study; . Dose Escalation Amendment: Newly established dose level . Status Change: Moving from Phase Ito Phase II; Closing or Opening a Arm; Temporary Suspension or Hold; re-opening the study along with other study changes; Version: March 2017

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. Scientific Changes: Adding a New Arm; Changing Objectives; Changing Statistical Analysis; Adding Correlative Studies; Increase or Decrease in Overall Accrual Goal; . Eligibility Changes: Changes to the Inclusion or Exclusion Criteria; . Therapy Changes: Change in Dose; Change in Administration; Change in Route of Administration; Change in Pre-Medications; Change in Drug Preparation; Change in Surgical Procedures or Radiation Administration; . Recruitment of Subjects: Change in the way subjects are recruited; New or revised study advertisement; . Data, Data Collection and Data Collection Materials: Revised documents given to subjects, including study diaries, questionnaires and QOL surveys; Adding new data points; . Editorial, Administrative Changes: Change in contact information; Change in site subjects; Typographical errors corrected; Clarifications made to previously approved research; . Other changes, as specified in the amendment form.

Change in Participating Study Staff or Site Participants Changes in participating study staff or site participants are submitted using the Research Team Update form, the Change in PI/Site PI form or the Request to Add/Remove Site form: . Change in the Principal Investigator or Site Investigator, including additions and removals; . Change in Research Team members including Co-Investigators, Research Nurses, Clinical Research Coordinators, including additions and removals; . Addition or Removal of a participating site.

Change in Study Status Changes in study status are submitted using the Closure/Re-Open form: . Permanent Closure to Accrual; . Temporary Closure to Accrual; . Closure of part of a study to Accrual; . Request to Re-open a Study to Accrual; . Change in Dose Level if the doses are already in the Protocol.

22.3 Amendment Submission Requirements General amendment submissions require a justification for the changes made to the study. The IRB requests that the justification be in lay terms and within the amendment form in order for the non-scientist IRB members to be able to understand the rationale for the proposed study changes. Without a sufficient justification within the amendment form, IRB review may be delayed.

All proposed changes to study documents must be clearly identified for the reviewers within the amendment form and/or submitted as a supplemental document such as a “summary of changes”. Without appropriate documentation of the proposed changes, review of the proposed amendment may be delayed.

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Section 23 – Reports of Non-Compliance (Deviations, Violations, Exceptions and Other Events)

23.1 Overview

During the conduct of the study, changes to the research may be proposed, or unintentional changes in the conduct of the research may be discovered. Changes to the IRB-approved study, planned or otherwise, are governed by federal and state regulations and Dana-Farber/Harvard Cancer Center (DF/HCC) Standard Operating Procedures (SOPs) for Clinical Research.

Investigators are also responsible for conducting human subject research in accordance with: . Dana-Farber Cancer Institute (DFCI) Institutional Review Board (IRB) reviews and determinations . DFCI IRB Policies and Procedures for the Protection of Human Subjects in Research . Office of Data Quality (ODQ) requirements . All applicable Regulatory Sponsor requirements

Non-compliance with the requirements identified above during the conduct of a research study may result in the report of a deviation, violation or exception or other event that must be reported to the DFCI IRB.

 A deviation is any prospective request to the IRB to deviate from the defined procedures set forth in the IRB-approved study, from DF/HCC policies and procedures, or from the regulatory sponsor’s requirements.

 A violation is a report to the IRB of a deviation which has already occurred and was not prospectively reviewed by the IRB prior to its initiation or implementation.

 An exception is a request to deviate from IRB-approved eligibility criteria and applies to cases in which a participant will be enrolled into a trial even though they do not meet all of the eligibility criteria. As a general rule, exception requests must be followed up by an amendment to the study in line with the proposed exception.

Planned ongoing study changes (amendments) to IRB-approved research must be submitted as a formal amendment and not as a deviation, violation or exception. Please refer to Section 22: “Changes to Previously Approved Research (Amendments)” for further information on amendments.

23.2 Major Deviations, Violations and Exceptions

The IRB further defines the severity of deviations and violations into “Major” and “Minor” categories. A major deviation/violation is one that impacts the risks and benefits of the study, impacts participant safety, affects the integrity of study data, or affects a participant’s willingness to participate in the study. A Minor Deviation/Violation is one that does not impact participant safety, compromise the integrity of study data or affect participant’s willingness to participate in the study. It is the responsibility of the Principal Investigator (PI) to determine whether a deviation or violation is major or minor and to ensure proper reporting to the IRB. Examples of major versus minor deviations/violations may be found within the OHRS Information sheet titled “Deviation/Violation/Exception and Other Event Reporting to the DFCI IRB”.

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Reporting Major Deviations/Violations/Exceptions

All Major Deviations/Violations/Exceptions are to be reported using the Major Deviation/Violation/Exception Form found on the OHRS website, and submitted to the IRB electronically via OHRS submit. All major deviations must be reported to the within five working days of when it is known that a deviation is anticipated. Major deviations should be reported as soon as possible before the event date so that the IRB has sufficient time to review and take action. All deviations should also include documented approval of the regulatory sponsor. All major violations must be reported within ten working days of discovery. Reports of deviations and violations should be submitted to the sponsor as outlined in the sponsor’s protocol.

IRB Review of Major Deviations, Violations, and Exception Requests Once the Major Deviation/Violation/Exception Form has been received by OHRS, it will be triaged and routed for either an expedited IRB review or review by the convened IRB. During the review, the IRB will determine whether the information in the report is sufficient and if the corrective action plan is appropriate. As a result of the review, IRB will make one of the following determinations:

1. No further action is required. The submission has been reviewed via expedited review procedures or at the convened IRB. It has been determined that the investigator’s assessment of the situation and the corrective action plan are appropriate and no further action is required. 2. Further action is required. The submission has been reviewed via expedited review procedures or at the convened IRB. Actions to be taken by the study team will be outlined by OHRS for the study team to respond to in a point-by-point manner and the response may be reviewed via expedited review procedures. 3. Refer to Full IRB. The submission and/or response has been reviewed via expedited review procedures and the expedited reviewer determines that the submission and/or response cannot be reviewed or approved on an expedited basis. The submission and/or response are then referred to the convened IRB for review for a determination. 4. Deferred - Further action is required. The submission has been reviewed by the convened IRB and actions to be taken by the study team will be outlined by OHRS in the minutes for the study team to respond to in a point-by-point manner. The study team’s response will then be re-reviewed by the convened IRB. 5. Disapproved. The submission has been reviewed by the convened IRB. The submission cannot go forward as requested.

The outcome of the IRB review will be sent by OHRS to the study team via email.

23.3 Minor Deviations/Violations

Minor deviations do not need to be submitted to the IRB for prospective review. Rather, they should be documented using the OHRS Minor Deviation/Violation Log. For sponsored trials, proper documentation of regulatory sponsor acknowledgement and/or approval for each minor deviation is required and should be kept with the log. If three or more minor deviations/violations of the same type (or for the same participant) are found in the Log and could impact the safety of participants, compromise the integrity of the study data and/or affect participant’s willingness to participate in the study, the events must be reviewed by the investigator confirming that they do not require immediate reporting to the IRB via the Major Deviation/Violation/Exception Form.

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The DF/HCC Lead Site is responsible for maintaining the minor deviation/violation log for all DF/HCC sites participating in the study and submitting it to the IRB with the continuing review form. A protocol that is approved and taking place at more than one site is still considered one protocol.

The Log can be found on the OHRS website and must be submitted no less than once per year at continuing review. The Overall PI is required to attest in the continuing review form that the minor deviations/violations have all been reviewed. If there are no minor deviations to be reported within the continuing review period, this must be indicated on the continuing review form. The IRB will review the Log at the time of continuing review and a determination regarding the Log will be made along with the continuing review.

23.4 Other Events

The Major Deviation/Violation/Exception and Other Event Reporting form may also be used to submit “Other Events” to the IRB for review that do not meet the definition of any other reporting category (e.g. an Adverse Event, Unanticipated Problem involving Risks to Subjects or Others, Deviation, Violation or Exception). These events may be reported to the IRB via the Major Deviation/Violation/Exception and Other Event Reporting Form at the direction of OHRS staff.

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Section 24 - Unanticipated Problems Involving Risks to Participants or Others

Unanticipated problems involving risks to participants or others can take many forms. The investigator or study staff must promptly receive all reports of unanticipated problems involving risks to participants or others.

The following items should be reported to the IRB:

1. Any adverse events that have all of the following characteristics: a. Serious (meaning an event that results in any of these outcomes or required medical intervention to prevent any of these outcomes: death, a life-threatening experience, inpatient hospitalization, prolongation of existing hospitalization, a persistent or significant disability/incapacity); and b. Unexpected (in terms of nature, severity, or frequency) given (a) the research procedures that are described in the protocol-related documents, such as the IRB-approved research protocol and informed consent document; and (b) the characteristics of the population being studied, and c. Related or possibly related to participation in the research (meaning that there is a reasonable possibility that the incident, experience, or outcome may have been caused by the procedures involved in the research); and d. Suggests that the research places participants or others at a greater risk of harm (including physical, psychological, economic, or social harm) than was previously known or recognized. Greater risk of harm is defined as a new or increased risk for which the IRB would require some action, such as informing participants or modifying the consent document.

2. Protocol violations (meaning an accidental or unintentional change to the IRB approved protocol procedures, including changes necessary to eliminate apparent immediate hazards to a study subject) that: a. Result in actual or potential harm to the participant; or b. Alter the potential for study benefit; or c. Have the potential to occur again.

3. Any event that requires prompt reporting to the sponsor.

4. Interim findings that indicate an unexpected change to the risks or potential benefits of the research. (For example, interim analysis indicates that the experimental group has an unexpectedly high rate of cure or an unexpectedly high rate of death.)

5. Publications in the literature that indicate an unexpected change to the risks or potential benefits of the research. (For example, a paper is published from another study that shows that the experimental arm of your research study is of no therapeutic value.)

6. Safety monitoring reports that indicate an unexpected change to the risks or potential benefits of the research.

7. Any complaint of a participant that indicates previously unforeseen risks, or any complaint of a participant that cannot be resolved by the research staff.

8. Any other event that indicates participants or others might be at risk of serious harms that were not anticipated. For example: a. A laptop with confidential information about participants in an AIDS study is stolen; b. A group email sent to your subjects accidentally discloses the names of all other subjects in the study; c. A subject in a group counseling session becomes emotionally upset and physically assaults a staff member; Version: March 2017

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d. The laboratory loses blood samples obtained to monitor critical serum drug levels; e. A member of the staff has a needle stick injury while drawing blood for a research study; f. Through blood typing or HLA testing done as part of a research study, a man unexpectedly discovers that he is not the father of his wife’s daughter; g. Subject use of a study related medical monitoring device miss-identified as a home confinement monitor resulting in detainment by law enforcement officers.

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Section 25 - Adverse Event (AE) Reporting

The DF/HCC overall PI must report any significant adverse events (AE) for drugs, biologics, or devices to the appropriate parties (i.e. IRB, sponsor, FDA, NIH). When applicable, the DF/HCC overall PI should notify the national study chair (i.e. for multi-center/cooperative group trials). The treating investigator is responsible only for notifying the DF/HCC overall PI of the incident. In cases where 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 time specified based on a start date equal to the date of notification to the treating investigator or DF/HCC overall PI (whichever is first).

25.1 Definitions

Adverse Event (AE):

Any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medical treatment or procedure regardless of whether it is considered related to the medical treatment or procedure (attribution of unrelated, unlikely, possible, probable, or definite). [NIH Guidelines, January 2001]

Any adverse drug experience, related to the research intervention, 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, any 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 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. [21 CFR 312.32(a)]

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). [21 CFR 312.32 (a)]

Unexpected Adverse Event: 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. [21 CFR 312.32(a)]

Attribution: The determination of whether an AE is related to a medical treatment or procedure.

Disability: A substantial disruption of a person’s ability to conduct normal life functions.

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25.2 Adverse Event Grading System

GRADING SYSTEM DESCRIPTION

Grade 1 Mild

Grade 2 Moderate

Grade 3 Severe

Grade 4 Life-threatening

Grade 5 Fatal

25.3 Attribution

ATTRIBUTION CATEGORIES DESCRIPTION

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).

25.4 DFCI IRB Reporting Requirements

The DFCI IRB reporting requirements are outlined in the OHRS Information Sheets:  Adverse Event Reporting  Review and Reporting of IND/IDE Safety Reports

Reminders when submitting AE reports to OHRS 1. Submission to OHRS will not satisfy any other reporting requirements (e.g. study sponsor, FDA, NIH/OBA, institutional Biosafety committees, etc. reporting requirements). 2. For confidentiality reasons, patient identifiers (e.g., name, medical record number, address) must not be included in the AE reporting form.

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25.5 Adverse Event (AE) Reporting Form

The AE Reporting Form must be used to report AEs experienced by DF/HCC participants enrolled in a DF/HCC study, including any adverse events on DF/HCC led Multi-Center trials where the event occurs at a non-DF/HCC site. The AE reporting form is available on the OHRS website. A complete written AE report must be submitted as required by the DFCI IRB policy.

If the Overall PI determines that the adverse event warrants a change to the protocol and/or consent form document(s), the AE reporting form must be submitted via OHRS Submit along with an amendment form.

25.6 NCI CTEP-AERS

The NCI AdEERS reporting process was replaced by the CTEP AERS program in March 2014. The CTEP- AERS form may be used in place of the DFCI IRB AE Reporting Form for NCI or cooperative group trials only.

Reporting via CTEP-AERS is available only through the Internet and can be found at https://webapps.ctep.nci.nih.gov/openapps/plsql/gadeers main$.startup

If the Overall PI determines that the adverse event warrants a change to the protocol and/or consent form document(s), the completed CTEP-AERS reporting form must be submitted via OHRS Submit along with an amendment form.

25.7 AE Follow-up Reports

When submitting a follow-up report to a previously reported AE or CTEP-AERS reporting form, please include information about all prior reports and any prior IRB determinations to the follow up report.

25.8 Gene Transfer Reporting Requirements

The PI is responsible for reporting all applicable adverse events to the NIH/OBA. Per the OBA Guidelines outlined in Appendix M-I-C-4 (http://oba.od.nih.gov/oba/rac/guidelines 02/NIH Guidelines Apr 02.htm), the following must be reported: 1. Any AE that is both unexpected and associated with the use of the gene transfer product; and 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. No later than 15 days of receipt by the investigator/sponsor for follow-ups for previously reported events; 4. Within 15 days of the determination that an event that occurs after the end of a trial is associated with the use of the gene transfer product; and 5. As soon as possible but no later than 15 days after the sponsor’s initial receipt of information of 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.

Submit the appropriate IRB form, after removing all patient identifiers, to the following: . Institutional Biosafety Officer . Sponsor, if applicable (the sponsor may have its own reporting form.)

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. FDA (if serious and unexpected, or death) . NIH/OBA

Note: 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 the OBA. The protocol document should outline the reporting policy.

25.9 PI-Initiated/IND Holder Reporting Requirements

If a DF/HCC investigator holds an IND/IDE on the agent/device, she must report directly to the FDA. She also has a responsibility to communicate that information to any other investigators conducting the trial under the IND/IDE.

Submit the Mandatory FDA Form #3500a (Mandatory MedWatch Form), available on the FDA website at http://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/default.htm, to the following: . FDA . Other investigators conducting trials under the IND/IDE

25.10 PI-initiated/Sponsor Holds IND Reporting Requirements

The sponsor, as the holder of the IND/IDE, is responsible for reporting serious adverse events directly to the FDA. In addition to the FDA Form #3500a (Mandatory Medwatch Form), the DF/HCC overall PI may also be required to complete a form supplied by the sponsor. The DFCI IRB reporting requirements may differ from the sponsor’s. DF/HCC investigators must comply with both.

25.11 Industry-sponsored (Investigational) Reporting Requirements

Refer to the above section entitled PI-initiated/Sponsor Holds IND Reporting Requirements.

25.12 Industry-sponsored (Commercial) Reporting Requirements

The Voluntary FDA form #3500 (MedWatch) may be used to voluntarily report an AE, potential and actual medical product errors, and product quality problems associated with the use of FDA-regulated drugs, biologics, devices, and dietary supplements. The form is available on the FDA website at http://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/default.htm. The sponsor of the trial, however, may have its own form.

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Section 26 - HIPAA

26.1 Health Insurance Portability and Accountability Act of 1996 (HIPAA)

The Health Insurance Portability and Accountability Act of 1996 (HIPAA) is the first comprehensive act of federal legislation dealing with the privacy of health information. The HIPAA Privacy Rule was created to provide strong protections that do not interfere with patient access to, or the quality of, health care delivery. The entire health care field is affected by the Rule, including research. Two subsequent pieces of legislation, HITECH and the Omnibus Rule have modified and updated HIPAA requirements but for purposes of this overview, the provisions of HITECH and the Omnibus Rule are included but not referenced separately. Under HIPAA, trial subjects are required to authorize the use and disclosure of their protected health information (PHI). According to the Rule, trial participants have the right to: 1. Access their PHI; 2. Request amendment of their PHI; 3. Receive an accounting of disclosures of their PHI; 4. Request restrictions on the uses and disclosures of their PHI; 5. Request receipt of communications of their PHI by alternative means or at alternative locations; and 6. Revoke their authorization for use and disclosure of their PHI.

Access: Research participants are entitled to access (i.e., inspect and copy) their PHI that is maintained in a designated record set. The Rule defines a designated record set as the provider’s health care and billing records about individuals and any records used by the provider to make health care decisions about individuals. Therefore, the designated record set includes PHI that is generated in research and recorded in the medical record or in billing records as well as PHI that is recorded elsewhere, such as the trial files, but is also used to make health care or billing decisions. It is important to note that information that is generated in research and lacks clinical validity or clinical utility generally will be considered outside the designated record set (unless it is recorded in the medical or billing records), and thus the Rule’s right of access generally does not apply to such information.

The Rule permits researchers conducting clinical trials to suspend participants’ rights of access temporarily, for as long as the research is in progress, if the participant specifically agrees to this suspension in the research authorization. The right of access must be reinstated when the research is complete.

Amend: Research participants are entitled to request that the researcher amend their PHI that is maintained in a designated record set. Participants may only amend PHI to which they have a right of access under the Rule. If the participant’s request to amend is granted, the researcher must inform the participant, the people or entities the participant identifies as needing the amendment and others who may rely on the information of the amendment.

Accounting: Research participants generally are entitled to request a list of disclosures by the researcher of any of their PHI (not limited to PHI in a designated record set) made over the previous 6 years in connection with the research. The right to accounting does not apply to disclosures of PHI made pursuant to the participant’s authorization or disclosures of limited data sets. However, the right to accounting does apply to disclosures of PHI made pursuant to a waiver of authorization (even disclosures pursuant to grandfathered waivers under the Rule’s transition provisions), disclosures of PHI in adverse event reports made without authorization, and disclosures of decedents’ PHI.

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2. The name of the person or entity who received the information, including address; and 3. A brief description of the PHI disclosed and a brief state of the purpose of the disclosure.

The Rule allows a “modified accounting method” for research that involves 50 or more people and for which authorization has been waived. For these large trials, the institution does not have to maintain a list of the specific persons about whom PHI has been disclosed but must make the following information available upon request to any individual who’s PHI may have been included: 1. The name and description of all protocols involving 50 or more people for which authorization has been waived, including the purpose of the research and the criteria for selecting records; 2. A brief descriptions of the type of PHI disclosed; 3. The dates or periods during which disclosures occurred; 4. Contact information for sponsors and recipient researchers; and 5. A statement that the individual’s PHI may or may not have been disclosed for a particular protocol.

In addition, the hospital or researcher must assist in contacting the sponsor and recipient researcher if it is reasonably likely that an individual’s PHI was disclosed to them. The Office of Information Security and Protection should always be contacted in the case of a data breach or disclosure in addition to notifying the IRB.

Restrict: Research participants are entitled to request that the researcher restrict the uses and disclosures of their PHI. However, the researcher is not required to agree to the restriction. If the researcher does not agree, the participant can decide whether she still wants to participate in the research. If the researcher does agree, the restrictions must be followed except if necessary to provide emergency treatment to the participant. Researchers must also communicate any restrictions to which they have agreed to other individuals or entities to which they permissibly disclose the participant’s PHI.

Alternate means or locations: Research participants are entitled to request receipt of communications of PHI from the researcher by alternative means or alternative locations (at a home address versus a work address). The researcher must accommodate such requests if reasonable but may require the participant to specify an alternate address or other method of contact. The researcher may not require the participant to explain the basis of the request.

Revoke: Research participants have the right to revoke their authorization for the researcher to use and disclose PHI in connection with the research, except to the extent that the researcher has already relied on the authorization. As a result, if the PHI has already been used to perform an analysis or other evaluation for the trial, the results of that analysis can be retained but the researcher must notify the IRB regarding the participant’s revocation. The researcher may also continue to use the participant’s PHI as necessary to account for the participant’s withdrawal from the trial or to report adverse events. However, the researcher generally may not use or disclose the PHI in new ways after the revocation. Researchers must inform other individuals or sites involved in the research of any revocation of authorization.

26.2 What Constitutes PHI?

The following are all considered PHI: . Names . Addresses . Dates that directly relate to the individual including birth date, death date, discharge dates . Telephone numbers . Fax numbers

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. Email addresses . Social security numbers . Medical record and pathology record numbers . Health plan beneficiary numbers . Account numbers . Certificate/license numbers . Vehicle Identification Numbers (VINs), serial numbers, and license plate numbers . Device identifiers and serial numbers . Uniform Resource Locator (URLs) . Internet Protocol (IP) addresses . Biometric identifiers including finger and voice prints . Full-face photographic images and comparable images . Any other unique identifier, characteristic, or code

26.3 “Minimum Necessary” Standard for Research Activities The Rule requires that researchers make all reasonable efforts to use or release only the minimum necessary identifiable health care information to achieve the intended purpose. The minimum necessary standard does not apply to treatment-related requests or disclosures of health care information or to situations in which an individual specifically has authorized the use or disclosure.

1. If a researcher obtains written authorization from subjects to use or disclose their PHI, the minimum necessary standard does not apply. However, the authorization must describe in a reasonably specific way what information will be used or disclosed, by whom and to whom, and for what purposes.

2. If the researcher requests that the IRB approve a waiver of individual authorization, then the minimum necessary standard applies. The researcher must describe in the waiver request specifically what health care information is necessary for the research. If the researcher requests access to electronic health care information, the researcher must identify the fields that will be requested to conduct the research. If the researcher requires access to paper records, then the researcher must identify the specific information that she will look for and retain to conduct the research. 3. Researchers using a limited data set must still apply the minimum necessary standard. The researcher must determine what types of data are necessary to conduct the research and must clearly describe those in the protocol submitted to the IRB/Privacy Board.

26.4 De-identified Information and the HIPAA Privacy Rule

PHI is considered not identifiable and not covered by the Rule if the information does not identify the individual and there is no reasonable basis for believing the individual can be identified from the information collected. The Rule outlines two ways in which information can be de-identified:

1. A person with appropriate statistical expertise can render information “not identifiable” if she can determine that the risk is very small that an anticipated recipient of the information could identify the individual by the information alone or in combination with reasonably available information. This same person must document the methods and results of the analysis to justify this determination; or

2. Alternatively, the following identifiers of the individual and his or her relatives, employers, or household members must be removed: a. Names

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b. Geographic subdivisions smaller than a state, including street, city, county, precinct, and ZIP code (the first three digits of the ZIP code can be used if its geocode includes more than 20,000 people; if not, then 000 must be used) c. All elements of dates, except year, related to an individual, including birth date, date of admission, discharge dates, date of death (for individuals greater than 89 years of age, year of birth cannot be used – all elements must be aggregated into a category of 90 or older) d. Telephone numbers e. Fax numbers f. Email addresses g. Social security numbers h. Medical record numbers and pathology record numbers i. Health plan beneficiary numbers j. Account numbers k. Certificate/license numbers l. Vehicle Identification Number (VINs), serial numbers, and license plate numbers m. Device identifiers and serial numbers n. Uniform Resource Locator (URLs) o. Internet Protocol (IP) addresses p. Biometric identifiers, including finger and voice prints q. Full-face photographic images and comparable images r. Other unique identifier, characteristic, or code

The IRB and the privacy committee will determine that these issues have been met prior to determining that data have been de-identified.

26.5 The Limited Data Set Option

The HIPAA Privacy Rule allows the use of select types of health care data without triggering all of its requirements. This option is available for research, health care operations, and public health purposes only.

Specifically, to use or disclose a limited data set, a researcher does not need an individual’s authorization. However, to ensure some privacy protections, researchers must use or disclose only the minimum necessary data to accomplish the purpose of the research.

The IRB will determine upon review whether the limited data set includes identifiable information. The IRB will determine whether consent can be waived.

The Rule defines a limited data set as PHI that excludes the direct identifiers of an individual or of relatives, employers, or household members of the individual previously listed in What Constitutes PHI.

Unlike the de-identified data set, the limited data set permits the inclusion of town, city, state, and ZIP code.

The limited data set also allows the use and disclosure of dates.

Important uses and restrictions for limited data sets: 1. The limited data set cannot be used to re-identify or contact individuals. 2. The minimum necessary standard applies to the limited data set. 3. The requirement for accounting for all disclosures of PHI does not apply. 4. Researchers using a limited data set must sign a data use agreement.

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26.6 Data Use Agreement Requirements

Researchers using the limited data set must agree to a data use agreement that describes the permitted uses and disclosure of the information received and prohibits any attempt to re-identify or contact the individuals.

The data use agreement will: 1. Establish that the data will be used for research and further uses or disclosures are not permitted. 2. State specifically who will be permitted to use or receive the limited data set. 3. Provide that the limited data set recipient will: a. Not use or further disclose the information other than as permitted by the data use agreement or as required by law; b. Use appropriate safeguards to prevent use or disclosure of the information other than as provided in the agreement; c. Report to the covered entity any identified use or disclosure not provided for in the agreement; d. Ensure that any agents, including a subcontractor to whom the limited data sets are provided, agree to the same restrictions and conditions that apply to the recipient; and e. Not identify or contact the individuals.

26.7 Accounting for Disclosures

Investigators and research teams must develop a system to account for disclosures of PHI. This accounting of disclosures must contain: 1. The date of the disclosure; 2. The name of the person or entity who received the information, including address; and 3. A brief description of the PHI disclosed and a brief state of the purpose of the disclosure.

This accounting must be maintained for six years. Participants may ask for an accounting of information unless they signed an authorization form within the consent form.

The Rule allows a modified accounting method for research that involves 50 or more people and for which authorization has been waived. For these large trials, the institution does not have to maintain a list of the specific persons about whom PHI has been disclosed, but it must make the following information available upon request to any individual whose PHI may have been included: 1. The name and description of all protocols involving 50 or more people for which authorization has been waived, including the purpose of the research and the criteria for selecting records; 2. A brief descriptions of the type of PHI disclosed; 3. The dates or periods during which disclosures occurred; and 4. Contact information for sponsors and recipient researchers and a statement that the individual’s PHI may or may not have been disclosed for a particular protocol.

In addition, the hospital or researcher must assist in contacting the sponsor and recipient researcher if it is reasonably likely that an individual’s PHI was disclosed to them. The DFCI Office of Information Security and Protection (or equivalent office at the participating institution) should always be contacted in the case of a data breach or disclosure in addition to notifying the IRB.

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26.8 Research on Deceased Persons

Identifiable health information of deceased individuals, including deceased participants in research, is protected by the Rule. The Rule extends privacy rights to decedents even though decedents are not considered human subjects protected under the Common Rule (regulations governing human subjects research). Specifically, the Rule allows researchers to access identifiable health information of decedents without obtaining participants’ or their representatives’ authorization, but only if a covered institution obtains certain assurances from the research with regard to that access. These assurances are that the: 1. Requested use and disclosure is solely for research on the protected health information of decedents; and 2. PHI for which use or disclosure is sought is necessary for research purposes.

For research using PHI from deceased persons, the IRB/Privacy Board will review the protocol. The investigator will be asked to document the following in the application: 1. Statement that the records are needed for research and will be used solely for research. 2. Entities (i.e., DFCI, Partners) may request documentation of deaths. Therefore, investigators should be prepared to provide such documentation upon request. 3. In cases when all participants are deceased, a waiver of consent and authorization will be granted if the investigator can show how the research meets those requirements. 4. In cases where a participant had been living but then dies during the course of the trial and authorization was obtained for purposes of the trial, the authorization will cover such continued use/disclosure. 5. Disclosures of decedent information must be tracked in accordance with the accounting requirements of the Rule. 6. The protection for deceased persons ends after the decedent has been dead for 50 years.

26.9 Waiver of Authorization for Research

Investigators will be required to apply for both a waiver of consent and a waiver of authorization to meet both requirements. The criteria for a Waiver of Authorization 45 CFR 164.512(I)(2)(ii) are: 1. The trial involves no more than minimal risk; 2. The waiver or alteration will not adversely affect the rights and welfare of the research participants; 3. The research could not practicably be carried out without the waiver of consent or alteration to the consent information; 4. Whenever appropriate, the participants will be provided with additional pertinent information after participation; 5. This trial involves no more than minimal risk to privacy:  The protocol includes an adequate plan to protect identifiers from improper use or disclosure;  The protocol includes an adequate plan to destroy the identifiers at the earliest opportunity. Identifiers may be maintained if there is a health or research justification or if law requires retention. The investigator must document such a justification and submit it to the IRB/Privacy Board for review and approval;  The protocol must include adequate written assurances that the identifiable information will not be reused or disclosed except as required by law, for authorized oversight of research, or for other research for which the use and disclosure would be permitted; 6. The research could not practicably be conducted without access to the use of this identifiable information.

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Section 27 - Biostatistics

The DF/HCC Biostatistics Core is a shared facility. One part of the core’s mission is to provide biostatistical expertise for the planning, conduct, analysis, and reporting of clinical trials and other investigations in oncology. Statisticians are available for consultation for all investigator-initiated trials conducted by the cancer center and for the review of protocols developed elsewhere. Staffing is allocated by disease program and/or modality and is provided by statisticians located at DFCI, MGH, BCH, BWH and HSPH. A list of statisticians assigned to various disease/modality programs is available www.dfhcc.harvard.edu/core-facilities/biostatistics/contact.

Please go to the OHRS website for biostatistical guidance relating to non-clinical protocols contained in the OHRS Information Sheet “Statistical Guidelines for Non-Clinical Research Protocols.”

27.1 Biostatistics Support for the Protocol Development Process

Ideally, the PI will meet with a statistician early in the development process to discuss possible primary endpoints, expected results in the population eligible for the trial, and preliminary sample size. Once the Disease or Disciple-based Program approves a concept for a trial, the PI meets with the statistician and other key staff to discuss the concept and review preliminary ideas, needs, sample size, and timelines for development. The statistician prepares a full statistical considerations section on this first draft. This includes identification of the primary endpoint, statistical justification of all sample sizes, and accrual duration. Plans for sequential testing and interim monitoring should be specified if appropriate.

The following is a checklist of things to consider in designing your trial or in considering participation in other trials. The statistician is an important resource in helping to address these issues.

 Is the phase of the trial consistent with its objectives?

 If the trial is a combination of phases, is the combination clearly justified? If applicable, does the design reflect both phases?

 Rules for reporting AEs should be consistent with the relevant phase(s) of the study.

 Are response definitions based on RECIST criteria? If not, have you provided a rationale for the criteria being used?

 Are toxicity assessments using appropriate criteria? Most trials should use the current version of the NCI’s CTCAE. If other terms or systems are being used, this choice should be justified.

 Is the statistical considerations section consistent with other parts of the protocol? Especially consider objectives, design, patient population, and endpoint definitions. The endpoint(s) used in the sample size justification should be based on the primary objective(s). Statistical considerations should be given for secondary objectives as well, where appropriate.

 Are the trial’s assumptions evidence-based? Assumptions regarding the null and alternative hypoth- eses should be consistent with the background and rationale, and hypothesized effects should be reasonable and attainable within the proposed trial. The “null” assumptions should be based on literature cited in the introduction or in the statistics section.

 Is the sample size appropriate? The statistician is your primary resource for information about appropriate sample size.

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o In trials with sample size based on a statistical test, type I and type II errors should be reasonable; levels beyond the usual range typically used in clinical trials should be clarified. If a one-sided test is used, the one-sided hypothesis should be justified adequately if the direction of the outcome cannot be determined a priority. o Phase I trials may have sample size based on the probability of dose escalation, the probability of seeing at least one toxicity of a given type, a confidence interval for the probability of a given type of toxicity, or the properties of a decision rule based on the percentage of subjects able to receive adequate treatment. If a Phase I trial has sequential dose escalation, then both the size of the cohorts started on a single dose and the number of additional subjects added at the MTD must be justified statistically. The probability coverage of a confidence interval (e.g., 95%) should be reasonable. The probability of increasing dose should be reasonable both for true rare probabilities of toxicity (large probability of dose increase) and for true common probabilities of toxicity (small probability of dose increase). o Phase II trials may have sample sizes based on a confidence interval or a decision rule for the primary endpoint. Again, the coverage probability of the confidence interval and the probabilities associated with the decision rule should be reasonable. Randomized phase II studies will often be designed around a formal hypothesis test, usually for a time-to- event endpoint (such as progression-free survival using a log rank test)

 Are early stopping rules incorporated into the design appropriately? Some reasons for a sequential design include: chance of serious toxicity, chance of a treatment having fewer effi- cacies than current standard therapies, a much larger than usual sample size, or anticipated slow accrual/long time to completion.

 If there is high probability of missing data for the primary endpoint, does the statistical considerations section address how they are being handled? This is especially important in questionnaire and psychosocial trials, in which subjects may leave some questions blank and in which a subject may not provide data at each of the protocol-specified times. If missing data may be correlated with worsening disease status, statistical methods must take this into account.

 If you are using questionnaires, have you provided data on the validity of the questionnaire and its reproducibility? Have you provided a reference for the scoring techniques? If the questionnaire is not part of the primary endpoint, the trial should describe how the questionnaire would be used.

 Is the statistical analysis plan clear about which subjects will be included in the analysis? The denominator for analyses should be specified (e.g. eligible participants, intent-to-treat [all participants as randomized], or required minimum therapy). Trials that exclude ineligible participants (or un-evaluable participants) from the analysis should specify the total number of participants to be enrolled.

 Is the trial clear about how stratification factors will be used? Single treatment trials should not have stratification factors but may accrue separately to two or more distinct cohorts. If the protocol proposes to stratify in order to analyze treatment within subgroups, sample sizes for the subgroups should be specified that are adequate for this. If stratification is being done for balancing purposes only, it is helpful to state this.

 Should secondary endpoints have sample size justification? Sample size justification may be appropriate for secondary endpoints, especially those that may result in additional pain, inconvenience, or cost to the subject (e.g., follow-up biopsies, scans, or tests that are not usually done for this disease). Unless required for treatment direction or eligibility, studies with mandatory biopsies will need to have statistical justification for the endpoints being studied using the biopsy material.

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27.2 Biostatistics Support for Forms Development

Most DF/HCC trials require unique electronic case report forms (eCRFs) to collect data. The CTRIO eDC team constructs draft eCRFs for the statistician and the PI to review. The PI, statistician, data manager, study coordinators, and any other relevant study personnel will meet to discuss the forms and to assess whether they are feasible and can collect the data necessary for all endpoints. Forms development should start as soon as possible.

27.3 Biostatistics Support for Data Collection and Storage

Mechanisms for data collection and storage vary from informal methods (e.g., non-computerized data, tables on word processors, data collected by a laboratory’s computer and transmitted via disk or email) to more formal methods, including case report forms provided by the CTRIO. Responsibility for maintaining the database could reside with the investigator, clinical data manager, nurse, secretary, and/or CTRIO. The statistician works closely with whoever is maintaining the data for data monitoring and quality assurance.

27.4 Biostatistics Support during Protocol Activation

If the trial involves randomized treatment assignments, the statistician must prepare randomization sheets so that treatments can be assigned through ODQ or research pharmacy. The PI should communicate with the statistician to ensure that randomization sheets are available at the time the protocol is activated.

27.5 Role of Biostatistics in Monitoring Active Trials

Statisticians participate with disease and discipline-based programs in monitoring accrual to active trials. If the statistical section of a trial has a monitoring plan based on toxicity rates or failures, the statistician is responsible for checking these outcomes and generating reports when necessary. If an interim-monitoring plan is part of the trial’s design, the statistician will conduct interim analyses and present results to the appropriate data monitoring committee as required.

27.6 Biostatistics Involvement in Protocol Addenda

Needs for protocol addenda may include changes to treatment, statistical design, consent form, eligibility, measurements of effect, and protocol schema. The statistician is responsible for any changes to the statistical section. These changes should be given to the statistician for review and then submitted to the OHRS by the PI for review and approval by the appropriate scientific review committee and the IRB.

27.7 Analyses/Reports on DF/HCC Trials

Data Monitoring Reports/Interim Reports

Generally, the statistician will prepare reports and/or present the report to a monitoring committee, if the trial has one. Currently, monitoring committees are required for all DF/HCC-initiated Phase III trials, randomized phase II trials and Phase I/II trials that are multi-site, are blinded, or employ particularly high-risk interventions or vulnerable populations. Trials that are done within the DF/HCC umbrella (e.g., DFCI, MGH, BIDMC, official affiliates, etc.) are not considered multi-site. Examples of high-risk interventions or vulnerable populations include vaccine trials or gene transfer.

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These reports generally consist of accrual, toxicity, and or outcome information. Once a trial has completed accrual, interim reports may continue to be written until the trial has matured enough for a final report. The DF/HCC Data and Safety Monitoring Board (DSMB) conducts a periodic review of the trial (essentially every 6 months). Interim analyses, in accordance with the trial’s sequential design, would be presented to the DSMB as appropriate. Most phase I and non-randomized phase II studies (that is, studies not being monitored by the DSMB) are reviewed by the Data and Safety Monitoring Committee (DSMC).

Final Analysis

The trial is ready for analysis when the conditions set forth in the statistical considerations section of the protocol for achieving the desired precision have been met and the data have been reviewed and finalized. These will vary by trial type and disease site.

The statistician is available to help with analyses of the results of PI-initiated trials if there are statistical analyses involved. If the report is straightforward and no statistical analyses are required (as with most Phase I trials), the statistician may not need to be involved. Investigators can contact the statistician to discuss the analysis plan.

Abstracts and Manuscripts

Statisticians take an active part in preparation of abstracts and manuscripts involving their trials. Note that with rare exceptions, data cannot be made public while a trial is still accruing participants, and in some cases, still following or treating participants. For Phase III and randomized phase II trials, DSMB approval must be obtained prior to submitting an abstract if the DSMB has not already released the data.

Statisticians should be given adequate time to complete the statistical work needed for an abstract or manuscript. Also, CTRIO and ODQ should be contacted in advance, when appropriate, so that the data can be prepared for analysis. For abstract submissions requiring data analysis, investigators should contact the disease site statistician at least one month prior to the abstract deadline. For abstract submissions involving statistical review only, at least two weeks should be allowed. For manuscripts, a mutually agreeable schedule should be worked out and agreed on by the investigator and the statistician before beginning the project.

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Section 28 – The Office of Data Quality (ODQ)

28.1 Introduction and Purpose The ODQ at DFCI was established in 1986 as the Quality Control Center (QCC). The QCC was charged with creating a standardized data management system for clinical trials. Over time the role of the QCC has expanded to include a variety of tasks, such as registering participants to clinical trials, managing Case Report Forms (CRFs), generating frequency and descriptive summaries for investigators, and generating vital statistical reports for DFCI and its partners.

In 1997, the Dana-Farber/Partners Cancer Center (DF/PCC) was established, uniting DFCI with BWH and MGH as one comprehensive adult oncology center. In 2000, BIDMC, Children’s Hospital Boston, Harvard Medical School, and Harvard School of Public Health joined with the DF/PCC to form the Dana- Farber/Harvard Cancer Center (DF/HCC). As a result, the DF/HCC Clinical Trials Support system was established and the QCC was renamed the Quality Assurance Office for Clinical Trials (QACT). In 2015 QACT was re-organized and divided into the Office of Data Quality (ODQ) and the Clinical Trials Research Informatics Office (CTRIO).

28.2 Mission

The ODQ supports the DF/HCC research community through the development and implementation of quality control, quality assurance, and process improvement programs. Our goals are to: 1. Verify that clinical trial data are accurate, reliable, and collected in a timely manner; 2. Ensure human subject research is conducted in strict compliance with applicable regulations and policies; 3. Promote policies and processes that are expeditious and practical through continuous evaluation and improvement; and 4. Provide the DF/HCC research community with superior customer service that is responsive, collaborative, and dependable.

28.3 Functions of the ODQ

Specific ODQ responsibilities include: . Up-front registration of participants on to selected therapeutic trials clinical trials and select ancillary trials clinical trials being conducted at the DF/HCC, its Affiliates, satellites and Multi-center external sites. . Review all Informed Consent Forms (ICF) and eligibility checklists for accuracy and completeness during the centralized registration process . Randomization of participants to treatment arms, when applicable . Monitoring of Phase I dose-escalation trials, when applicable . Protocol accrual monitoring for rapid and slow accrual . Providing statistics for the DF/HCC

. Database table design and maintenance as well as eDC implementation . Management and monitoring of DF/HCC protocols for data collection using paper Case Report Forms (CRFs) and those using Electronic Data Capture (EDC) Development of protocol-specific quality-control procedures for maintaining high quality data acquisition

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. Maintain documentation of database design and functionality . Management of a peer-reviewed Internal Auditing Program ensuring protocol and regulatory compliance of on-going clinical trials across multiple disease groups and types of sponsorship . Presentation of final audit reports and audit summary results to the DF/HCC Audit Committee for clinical and regulatory review prior to final reporting to the investigator and study team. . Administer an internal Educational Program providing training on Human Subjects Protection, conduct of clinical trials, institutional policies and federal regulations. . Development and maintenance of the DF/HCC Standard Operating Procedures which guide research across the consortium . Registration of trials and accruals to NCI Clinical Trial Reporting Program (CTRP) . Facilitation and tracking of clinicaltrials.gov registrations for investigator-initiated trials . Coordination and administrative management of several Institutional Oversight Committees: o Clinical Investigations Leadership Committee (CLC) o DF/HCC Audit Committee o Clinical Trials Operations Committee (CLINOPS) o Data Safety and Monitoring Committee (DSMC) for high-risk Phase I, I/II, and II trials o Data Safety Monitoring Board (DSMB) for large randomized trials o Multi-center Coordinating Committee (MCC)

28.4 Participant Enrollment in Clinical Trials

Prospective Participant Registration by the ODQ

For applicable clinical trials, prior to the initiation of any protocol required test, procedure or intervention, all participants must be registered in the clinical trials management system, OnCore. OnCore has an electronic registry of all patients on DF/HCC oncology protocols, and serves as the master list for generating protocol summary statistics, drug dispensing, NCI reporting, and auditing. OnCore also allows for monitoring accrual rates, a crucial determinant of whether a protocol will meet the accrual objectives outlined in the protocol.

An investigator, treating physician, research nurse, or study coordinator listed on the Delegation of Authority Log (DAL) is responsible for registering participants in OnCore.. Applicable trial registration involves faxing the IRB approved, signed and dated ICF and fully completed protocol specific eligibility checklist to the ODQ.

Note: treating physicians cannot order drugs if a participant is not registered in OnCore. Likewise, if a participant is not removed from protocol, the physician cannot order any non-protocol therapy.

Retrospective Registrations

Retrospective registrations for therapeutic protocols are not allowed. For some minimal-risk trials, where a high volume of participants are recruited daily, registrations are accepted retrospectively in batches by fax or mail. In these cases, the study team needs to prospectively seek approval from the ODQ Director.

Eligibility Checking Process

Protocol-specific eligibility criteria are established to prospectively identify appropriately qualified subjects from the target population and to ensure patient safety by identifying those that are ineligible. When an investigator identifies a potential trial candidate, she must confirm and document in detail if the candidate is

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eligible to participate in the trial. For applicable trials, the ODQ registrars review the eligibility checklist for completeness prior to enrollment. However, the eligibility checklist is not considered source documentation and the acceptance of the checklist at the time of registration assumes that the treating physician has reviewed, confirmed and documented all subjective criteria (i.e. laboratory test, histology reports) and objective criteria (i.e.co-morbidities, life expectancy, performance status) prior to registration.

The completed eligibility checklist is faxed to the ODQ along with the entire signed consent document. The ODQ registrar confirms that all fields on the checklist are complete and that all values are within the acceptable range allowed by the protocol. The ODQ will not register a participant in the absence of complete information. All tests that are required to determine eligibility must be completed within the time frame specified in the protocol.

If a time frame is not specified in the protocol, tests must be completed as follows:

. Lab tests required for eligibility must be completed within 14 days prior to registration by the ODQ. For protocols requiring tumor metrics or measurable disease, baseline measurements must be completed within 14 days prior to registration by the ODQ. Examples: flow cytometry, HLA typing, fluid cytology, tumor markers, and hormones (CEA, CA-27-29, CA-125). . Non-lab tests required for eligibility must be performed 30 days prior to registration. Example: Radiological scans. . For bone marrow transplant (BMT) protocols and non-protocol treatment plans, eligibility tests must be completed within 42 days prior to registration. The extended period of time is allowed to facilitate insurance approval while ensuring participant safety.

Development of Eligibility Checklists

For applicable clinical trials, when a research protocol is activated or amended, the ODQ registrar generates a new checklist or revises an existing eligibility checklist from the protocol document posted to the Oncology Protocol System (OncPro). For cooperative-group trials or industry-sponsored trials that may generate their own checklists, the ODQ develops a “front sheet” to capture additional information not found on the checklist, such as patient demographics, lab values, test dates, randomization arms and dose levels for Phase I dose- escalation trials.

The registrar notifies the OHRS online team that a checklist has been generated for posting. In the case of front sheets, the cooperative group or sponsor’s checklist is posted by the OHRS online team.

Consent Checking Process

Physicians delegated to obtain informed consent on an IRB approved, activated protocol, are required to obtain informed consent from a participant (or the appropriate legally authorized representative) before enrolling him or her in a clinical trial. Written consent must be documented on the currently approved IRB consent form posted on OncPro. For applicable trials, all pages of the consent must be faxed to ODQ along with the eligibility checklist for participant registration, unless otherwise specified in the protocol, in which case the protocol registrar will enter an explanatory comment in the OnCore System. If a consent form contains embedded questions, all questions should be answered for the form to be considered complete. Any embedded questions left unanswered are considered to be non-consent.

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An expired or invalid consent form will be not accepted by ODQ. If ODQ receives an expired or invalid consent form, the protocol registrar will notify the registering person and/or the person who obtained consent that the participant must be re-consented before she can be registered.

All pages of the consent form must bear unique patient identifiers. All appropriate signatures and dates are required for consents to be considered valid. When appropriate, the short form of the consent may be required for non-English speaking subjects.

Per the DF/HCC SOP on consent, the informed consent document must be presented by an individual who is: (1) trained in human subject protections; (2) trained on the protocol; (3) listed on the Delegation of Au- thority Log; and (4) for all interventional drug or device research, must be an attending physician.

28.5 Randomization Process

The protocol registrar is responsible for randomizing participants to treatment arms for applicable studies, typically PI-initiated protocols. The protocol registrar is instructed by the statistician in the Department of Biostatistics Sciences on how to conduct the randomization. The ODQ designee then documents the instructions in OnCore, to which the protocol registrar will refer. Unless the protocol is blinded, the protocol registrar documents the specific patient randomization assignment in OnCore. If the protocol is blinded, the protocol registrar conveys the randomization assignment to the appropriate departments (i.e. pharmacy) as indicated by the randomization instructions.

28.6 Phase I Dose-escalation Trials

For applicable clinical trials, the protocol registrar is responsible for monitoring all investigator-initiated Phase I, or Phase I/II trials. The dose-escalation schema, when included in the protocol, is documented in OnCore. If a specified waiting period between and within cohorts has not been met patient assignment to the next dose level or cohort will be denied. The IRB must approve revisions to the protocol if additional patients, cohorts, or dose-levels are to be added. The protocol registrar ensures that the dose-escalation schema is followed exactly as it is written and appended in the protocol.

28.7 Single Patient IND

An individualized IRB approved consent form must be signed and faxed to the ODQ for Single patient IND protocols. Data collected through this process can’t be used for analysis if associated with a main protocol.

28.8 Non-protocol Standard Treatment Registration

Some participants may be registered on a standard regimen that is not part of a clinical research trial. The regimen may be commercially available drugs or a specific procedure. ODQ designates all treatment plans in OnCore by the protocol naming convention: TP-###.

28.9 DF/PCC Network Affiliate Registration

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For DF/PCC network affiliates participating under their own IRB, consent must be obtained on a current, IRB approved consent form from the IRB of record for the affiliate institution. The completed - eligibility checklist must accompany the consent.

The protocol registrar will not register a participant from a non-DF/HCC institution, unless that has appropriate DFCI IRB approval.

28.10 Industry-led and Cooperative-group Registration

For industry-led and cooperative-group trials, registration must occur at the sponsor/cooperative group level before registering with the ODQ. For applicable trials, egistration with the ODQ must still occur prior to the conduct of any study related activities. The ODQ will not register a participant from an outside institution on a sponsored trial unless IRB-approval has been obtained.

For participants enrolling in cooperative group trials for treatment at a DF/HCC institution, the ODQ- generated front sheet (or checklist) must accompany the consent.

28.11 Non-patient Volunteer Registration

Non-patient volunteers undergoing invasive procedures or administration of pharmacologically active substances must sign a consent form and register with ODQ. Blood draws are exempt. Bone marrow aspirates are not exempt.

28.12 Electronic Confirmation of Registration

After a participant is registered to a protocol, confirmation of registration is automatically sent to the person who submitted the registration, the Overall PI, treating physician, and main study contact listed on the front sheet. Hard copies are generated upon request.

28.13 After-hours Registration

ODQ’s normal business hours are 8:30 AM to 5:00 PM EST. Patients are enrolled and randomized in clinical trials or non-protocol treatment during normal business hours, unless an emergency arises in which a participant must be treated before the next business day.

To register a research subject after-hours call the ODQ main number, (617) 632-3761, select option one, leave a detailed description of the participant’s eligibility and a call-back number where the registrar on-call can reach the responsible study staff. At this time, also fax the signed consent form and completed eligibility checklist to the ODQ. Registration occurs off-site after normal business hours. An ODQ registrar on call will contact the caller to complete the registration.

28.14 Removing a Participant from a Research Study

When a participant will no longer be treated and/or followed on protocol and no further data will be collected directly from the subject, the ODQ registrar must be officially notified via, fax or email by submission of the ‘Treatment Ended & Off Study Form’. The trial number, the reason the participant is being removed from the

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trial, the effective date, as well as the date treatment ended (if known) must be specified. The protocol registrar then removes the participant from the trial by updating the subject’s record in OnCore.

Orders for drugs administered as part of a DF/HCC research protocol are electronically integrated with OnCore. Protocol administered drugs can only be dispensed when a research participant has been registered to a specific study in OnCore. This safety mechanism ensures that no research drug can be dispensed in the absence of a valid protocol registration for the identified participant. The system also ensures that a research subject can only be registered to one therapeutic protocol at a time and will block any attempts at creating duplicate registrations or multiple registrations to therapeutic trials. However, a participant may be enrolled in more than one minimal-risk ancillary trial at any given time.

If a participant is not removed from a therapeutic protocol, non-protocol therapy cannot be ordered and the subject cannot be registered to another therapeutic protocol. If the participant must be treated on a different therapeutic trial but the off- trial date is unknown, the protocol registrar will enter an off-trial date 1 day prior to the registration date of the new trial. The protocol registrar will document the reason as “other – switched to other protocol” in OnCore.

28.15 Protocol Closure Notification

The DFCI IRB Study Closure/Re-Open Form must be completed and sent to OHRS. Once approved by the IRB, OHRS notifies the ODQ that the protocol is closed to enrollment for any reason.

For trials open to accrual prior to 2009, paper copies of the registration documents (eligibility checklist and consent document) are maintained by the ODQ. For trials open to accrual after 2009, electronic copies of the registration documents (eligibility checklist and consent document) are maintained by the ODQ. When deemed appropriate, protocol registration files are moved to an off-site storage facility. If those records are needed, the ODQ Director must be notified and the documents will be retrieved.

28.16 Protocol Completion/Termination Notification

When a protocol is terminated or completed because data analysis is complete and no further research will take place the Overall Principal Investigator must notify the IRB by submitting a DFCI IRB Study Completion Form. Before the submission can be accepted by the DFCI IRB, ODQ must ensure that all subjects have been taken off-treatment and off-study in OnCore.

Once ODQ has confirmed that no further study data is needed and all subjects have been taken off study, the DFCI IRB will review the study completion submission. Once accepted by the IRB, ODQ and the Study Team then receives notification from OHRS that the submission has been accepted and no further research will take place.

28.17 Reports Available from the Clinical Trials Research Informatics Office (CTRIO)

Upon request, the CTRIO can compile a variety of reports on protocol data metrics.

Examples of CTRIO generated reports:

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. Protocol accrual reports containing summary information about each participant registered.. These lists can be provided based on preferred listing criteria, i.e. dates of registration, alphabetically by subject name, protocol ID or medical record number. Accrual reports can also be generated for specific time periods, across multiple protocols, disease type(s), phase, sponsor, race, gender, ethnicity, and service area.

Upon request, custom reports can be provided based on specific criteria.

28.18 Protocol Accrual Monitoring

For applicable clinical trials, the ODQ Registrars monitor accrual in real time and notifies the study team when the protocol is nearing target accrual.

28.19 Case Report Form (CRF) Design

Accurate collection of protocol and non-protocol data is essential to ensuring the integrity and evaluability of the scientific objectives and end-points of a research protocol. CRFs provide a standardized method of collecting clinical research data. CRF design refers to the process of identifying what data must be collected to meet trial objectives by creating an electronic data capture scheme and interface for inputting necessary data. When a proposed study is submitted to OHRS, a CTRIO designee is assigned to review the protocol document and prepare sample forms which are provided to the Overall Principal Investigator, study team, and biostatistician (when applicable) for review.

The study team, CTRIO EDC team, ODQ data analyst, and statistician work together to finalize a set of CRFs so that all necessary data is appropriately collected. CRFs must be finalized and approved prior to activation.

Data Collection

Data collection involves reviewing medical information that has been abstracted by a Study Coordinator and transcribed onto CRFs. Ultimately, the PI assumes the overall responsibility for data that are collected, but the ODQ data analyst monitors the data for quality and consistency.

Data Requests

Data requests must be made in writing to CTRIO and have the approval of the PI. The request form must be filled out completely to expedite the request. A minimum of one week for programming should be allowed, depending on the request. If the data request has not been processed and keyed, allow two to four weeks. All requests require programming time and effort; therefore, careful consideration should be given to the request information in advance.

Biostatisticians require ample time to conduct a thorough review of all the trial endpoints and issues. Last- minute requests for data analysis should be avoided.

Incomplete Forms/Missing Forms/Queries

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The ODQ data analyst is responsible for creating and generating a missing forms report on a regular basis to monitor the data collection process. The ODQ data analyst can request missing information thru individual or participant-specific data queries, or thru direct communication with the study team and/or biostatistician (typically done when the data is being prepared for analysts).

28.20 Documentation and Storage of Data

Storage Procedure

Data for protocols where data is recorded on paper are stored on-site at the ODQ offices. Once the paper CRFs have been reviewed, submitted, and appended to the database, they are filed. The study coordinator keeps copies of the paper CRFs in their research files. Paper CRFs are the written record documenting information that has been submitted to ODQ and stored in the Ingres database. All forms for a given protocol are stored on-site at ODQ while that protocol is active. Forms collected for protocols that are completed are housed at an off-site storage facility.

The Department of Biostatistics conducts nightly backups of all computer data in Ingres.

28.21 Accrual-monitoring Program

Accrual monitoring is managed by the Scientific Review Committee (SRC) based upon information provided by the ODQ. Protocols are monitored for slow accrual, rapid accrual, and zero accrual. The SRC has the authority to close a trial for accrual problems.

28.22 Internal Auditing

ODQ Clinical Trials Audit Manual http://www.dfhcc.harvard.edu/crs- resources/conduct/forms_and_templates/ongoing_research_documents/forms_policies_and_manu als/Audit_Manual_March_2014.pdf

The DF/HCC internal auditing program oversees the compliance of the clinical trial process. The purpose of the internal audit program is to ensure a high standard of quality for DF/HCC protocols by systematically evaluating:

1. Protocol Compliance 2. Protection of Human Research Participants 3. Institutional SOPs, ICH Good Clinical Practice Guidelines and Federal Regulations Compliance 4. Data Accuracy 5. Investigational Drug Handling 6. Appropriate reporting to regulatory authorities

Each Clinical Research Auditor selects a minimum of two protocols a month to audit. All active DF/HCC protocols are eligible for audit, including those protocols sponsored by the NCI, cooperative groups, pharmaceutical industry or other sponsors. The following rubric is used for prioritizing protocols to audit:

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. Human Gene Transfer protocols are audited annually; . In-house interventional & NCI/NIH funded protocols are audited a minimum of once in their lifetime; Priority is given to high-risk studies. Disease and discipline-based programs are chosen on a rotating basis and a protocol is eligible after five participants have been accrued, unless the target accrual is less than 10 participants; . Industry and Cooperative Group trials: Annually, a minimum of one industry and cooperative group trial will be audited per disease or discipline-based group; . DF/PCC Network Affiliate hospitals are audited annually after at least two participants are registered on a study; . For cause audits of protocols requested by CLC, IRB, DSMC or DSMB including re-audits. . Protocols identified as rapidly accruing by the Accrual Monitoring Program (expected duration less than one year or accrual rate is 1.5 times faster than expected); . Protocols identified as having new DF/HCC Overall PIs or new clinical research investigators per the DF/HCC SOPs EDU-104 and EDU-105.

Each DF/HCC disease group will be audited a minimum every three to six months. An Overall Principal Investigator (PI) who is audited once during the year may be audited a second time during the year on a different protocol.

The Clinical Research Auditor selects protocols from a list of eligible studies and disease sites. The auditor attempts to distribute the audits evenly among the various disease programs and protocols including those protocols that address multiple disease groups.

The Clinical Research Auditor uses the protocol document as the basis for evaluating protocol compliance. The specific areas are:  Regulatory  Informed Consent  Registration and Randomization  Eligibility  Pre-Therapy Requirements  Treatment Administration  On-Study Evaluations  Response Evaluations  Adverse Events  Data Collection  Investigational Drug Handling

The DF/HCC Audit Committee reviews the audit findings and approves or disapproves of the violations and audit rating. The Overall PI is requested to respond in writing with a corrective action plan to any major violations noted during the audit. The Audit Committee will review and approve the corrective actions plans as appropriate, or may request additional information from the Overall PI. Documentation is maintained in the ODQ.

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The Manual describes the auditing process in detail. All clinical researchers and data management staff are advised to become familiar with the importance of and the procedures for audits. Seminars are arranged annually through ODQ to familiarize staff with the audit process and assist them in preparing for an audit.

28.23 DF/HCC Data and Safety Monitoring Board (DSMB) The DSMB was formed to review large randomized trials in accordance with NIH/NCI requirements. The DSMB monitors trial progress and potential risks to participants enrolled in protocols that are developed by DF/HCC investigators. Board members are by majority external to DF/HCC in addition to clinicians and biostatisticians representing the DF/HCC. The DSMB meets semiannually and reports its findings to the CLC and the IRB.

28.24 DF/HCC Data and Safety Monitoring Committee (DSMC) The DSMC for pilot, phase I, I/II, and Phase II trials provides ongoing monitoring for high-risk clinical trials initiated and conducted by DF/HCC investigators to ensure the safety of trial participants as well as to evaluate the ongoing status of the trial. Membership is appointed by the senior vice-president for research and includes:

Voting members:  3 medical oncologists  1 ad hoc physician as needed (i.e., radiation oncologist, surgeon)  1 biostatistician  1 nurse  1 pharmacist  Chair will be one of the physicians

Non-voting member:  1 coordinator for meetings

The ODQ serves as administrative support to the committee. Information provided to the committee includes: current accrual, reporting of all adverse events including, any response information that is available, and a summary provided by the study team. Other information (e.g., scans, laboratory values, participant charts) will be provided if requested by the committee. Minutes are kept and recommendations are made to the study teams and reported to the IRB and CLC. All trial and participant information is kept confidential. All DSMC members sign a confidentiality and conflict of interest (COI) statement related to the trials being discussed. Members will recuse themselves from the discussion and voting if a conflict exists for a given protocol.

Protocols that require monitoring are high-risk DF/HCC-initiated protocols. The study team, SRC, pediatric SRC, IRB, and/or CLC identify them. High-risk protocols may include, but are not limited to, gene-transfer trials, vaccine trials using live or attenuated viruses, new therapies being tested for the first time in humans, trials initiated within the DF/HCC but conducted at multiple centers outside the DF/HCC, or trials that are exceptionally complicated or intensive. Most high-risk sponsored trials initiated outside of the DF/HCC have their own monitoring committee. If these trials do not have a DSMC and if the DF/HCC review committee determines that an increased level of monitoring is required, then they will also be reviewed by this committee.

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Section 29 - Clinical Trials Education

Education in the conduct of human research and clinical trials is essential to protecting the rights and welfare of individuals participating in cancer research studies. In recognition of this principle, ODQ provides centralized education services for the DF/HCC research community. ODQ offers initial and continuing education opportunities designed to support, develop and maintain a standardized body of knowledge and best practice methodology.

In addition to the compulsory training in human participant protections, the curriculum includes traditional lectures, seminars, and online instruction to enhance the overall knowledge of DF/HCC investigators and study staff. The multi-faceted programs aim at ensuring Good Clinical Practice (GCP) in the conduct of cancer-related research and compliance with all applicable Federal regulations, state laws and local guidelines.

29.2 Programs for Clinical Investigators

New Clinical Investigator Training

This training session, designed for investigators conducting research for the first time or those new to DF/HCC, provides an introduction to NCI requirements, DF/HCC policies, and DFCI IRB guidelines and reporting requirements pertinent to the research initiatives at DF/HCC. New clinical investigators are required to complete this one-time training prior to acting as Principal or Site-Responsible Investigator of a DF/HCC clinical trial. For more information, please contact [email protected] or call 617-582-8480.

DF/HCC Clinical Investigator Education Series

The DF/HCC Clinical Investigator Education Series utilizes lectures, interactive discussions and/or case studies to disseminate:

. Underlying principles and procedures for conducting clinical trials . Current information on topics related to the conduct and management of oncology clinical trials . Best practice information, including meeting the standards of Good Clinical Practice (GCP), that can be incorporated into the workplace

For more information on the series, including upcoming topics and category 1 CME information, please contact [email protected].

29.1 Programs for Study Team Members

As a service to the DF/HCC disease and discipline-based programs, ODQ takes a proactive approach and works with other research entities to provide initial and ongoing education to study team members. To ensure the safe conduct of clinical trials within DF/HCC, the following educational opportunities are available to DF/HCC study team members.

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Orientation Support for New Research Staff

New DF/HCC research staff are trained by their individual institution clinical trials office. Additional educational materials are available on the DF/HCC website.

Research Education Series

This continuing education series is designed for DF/HCC study team staff. Topics focus on 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 sessions are generally offered at the Dana-Farber Cancer Institute for institutions in the Longwood Medical Area, and at the MGH Cancer Center Protocol Office.

In an effort to improve educational offerings for experienced staff involved in clinical trials, contact hours are offered when applicable.

29.4 eLearning Center

The objective of eLearning Center is to ensure that DF/HCC investigators and study team members have access to clinical trials education at a time, and in a manner, convenient to them. eModules

Focusing on a variety of topics related to human participant research at DF/HCC, these brief voice-over PowerPoint presentations are a quick and easy way to review basic information and expectations about DF/HCC research processes and compliance.

More eModules are in development. If you have a suggestion for a new topic, or have any comments, contact the ODQ Clinical Trials Education Coordinator at [email protected].

Presentation Archive

Learners can tab through select DF/HCC Clinical Investigator Education Series and/or Research Education Series Powerpoint presentations from the last three years.

29.5 In-services

ODQ staff is available to participate in conduct small group in-services and round table discussions addressing a variety of topics relating to study conduct, DF/HCC policy, and good clinical practice. These sessions are planned at a time and location convenient to the attendees. For more information, please contact [email protected].

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Section 30 - NCI Investigator Registration and Renewal

National Cancer Institute (NCI) investigator numbers are required for all Dana-Farber/Harvard Cancer Center (DF/HCC) attending physicians who will obtain consent from subjects for research related therapy or who will write orders for research related therapy. The NCI investigator registration process is centralized in the Of- fice of Data Quality (ODQ).

Upon the directive of the NCI, the DF/HCC has implemented a centralized process for obtaining and updating NCI investigator status. The process includes the annual completion of an NCI-specific FDA form 1572 accompanied with a current CV. The NCI also requires the completion of a supplemental Investigator Data Form (IDF) and Financial Disclosure Form (FDF). The ODQ works on behalf of the NCI-designated registration coordinator (ODQ Director) to update all DF/HCC investigators annually. The deadline for renewal of all DF/HCC investigators, regardless of when they initially registered, is August 1st.

The ODQ coordinates the renewal process, which begins every June. Investigators are advised to return all completed documents to the ODQ. ODQ staff will confirm that all required fields are completed and all signatures are obtained prior to sending the documents to the NCI.

New investigators who need to register with NCI should contact the [email protected] obtain the registration materials. It is important that they register through the ODQ so their names can be added to the annual DF/HCC registration list. New investigators can register at any time during the year but need to renew their registration during the annual registration period (June-August) regardless of the time of initial registration.

More information about this process can be found on the DF/HCC website.

Note: NCI registers surgeons, radiation oncologists, and other oncologists. Generally, the NCI does not register fellows, dentists, pathologists, and psychiatrists.

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Section 31 - Protocol Registration Requirements

Clinicaltrials.gov U.S. Public Law 110-85-FDAAA-801 http://clinicaltrials.gov/ct2/manage-recs/background, along with the International Committee of Medical Journal Editors (ICMJE), requires registration of clinical trials on a publicly-accessible database. The National Library of Medicine maintains the preferred registry (ClinicalTrials.gov) at: www.clinicaltrials.gov

Clinical Trials Reporting Process

As an NCI-designated comprehensive cancer center, DF/HCC is also required to register all interventional, observational and correlative trials, regardless of funding type, to the Clinical Trials Reporting Program (CTRP). The ODQ registers, maintains and updates the clinical trials that are registered on CTRP.

31.1 Clinicaltrials.gov Protocol Registration

Clinicaltrials.gov requires that all interventional clinical trials be managed and validated locally before they are published within the system. Clinicaltrials.gov registration occurs after IRB approval and a Clinicaltrials.gov record number must be assigned prior to accrual activation There is shared responsibility between the sponsor and lead investigator to register the trial. Investigators and study staff may refer to the chart below for guidance.

RESEARCH TYPE PROCEDURES

Industry-initiated and-funded Contact the pharmaceutical sponsor to determine the registration responsibility.

Federally funded (includes NIH, CTEP, Contact http://ctep.cancer.gov/ directly. Instructions and NCI Cooperative Groups) on how to submit information are available at http://ctep.cancer.gov/

In-house, investigator-initiated The ODQ initially registers all PI Initiated interventional trials regardless of phase controlled by the DFCI IRB. For questions, please refer to DF/HCC Contacts for Clinicaltrials.gov Accounts and Initial Registration, http://www.dfhcc.harvard.edu/fileadmin/DFHCC_Ad min/Clinical_Trials/CTEO/downloads/DFHCC_Conta cts_for_ClinicalTrials.gov_Accounts_and_Initial_Reg istration.pdf or contact [email protected]

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Protocol Registration Maintenance

Public Law 110-85 FDAAA-801 and ICMJE also require the routine update and verification of the information posted. The responsible party is required to maintain and update the record. Clinicaltrial.gov records need to be updated within 30 days of any recruitment changes and the information must be verified every 6 months

Please refer to the DF/HCC Clinicaltrials.gov website for information on how to maintain a Clinicaltrials.gov record http://www.dfhcc.harvard.edu/clinical-research-support/quality-assurance-office-for-clinical-trials- qact/clinical-trial-registration/

Posting Protocol Results

Public Law 110-85-FDAAA-801 also requires the posting of results for all “Applicable Trials” on clinicaltrials.gov. Results are required to be posted within one year from the completion of the primary outcome. For additional information, please refer to DF/HCC SOP SS-301, DF/HCC Clinicaltrials.gov website http://www.dfhcc.harvard.edu/clinical-research-support/quality-assurance-office-for-clinical-trials- qact/clinical-trial-registration/ and Clinicaltrials.gov website http://clinicaltrials.gov/ct2/manage-recs/how- report. For questions, please contact [email protected]

31.2 Clinical Trials Reporting Program (CTRP)

NCI’s Clinical Trials Reporting Program (CTRP) requires the registration of trials within 21 days after activation, amendment submission with 20 days of IRB approval and accrual information quarterly. This process is centrally maintained within the ODQ. Contact the ODQ with any questions regarding the CTRP [email protected].

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Section 32 - Principal Investigators

The Principal Investigator (PI) has ultimate responsibility for the conduct of the research trial. The duties of a PI are outlined in the FDA form 1572 in section 9 entitled “Commitments.”

32.1 General Responsibilities of the PI

The PI is responsible for:  Conducting the trial in accordance with the relevant, current protocol and only making changes to the protocol after notifying the sponsor (if applicable) and the IRB, except when a delay to notify the sponsor might compromise the safety, rights, or welfare of participants;  Conducting the trial in accordance with the investigational plan, institutional policies, and all applicable regulations;  Personally conducting or supervising the trial;  Informing trial participants that the drugs/devices are being used for investigational purposes and ensuring that the requirements relating to obtaining informed consent and IRB review are met;  Reporting to the sponsor and the IRB any adverse events (AEs) that occur in the course of the trial;  Reading and understanding the information in the investigator’s brochure, including the potential risks and side effects of the drugs/devices;  Ensuring that all associates, colleagues, and employees assisting in the conduct of the trial are informed about their obligations in meeting these commitments;  Maintaining adequate and accurate records in accordance with all regulations and requirements and making those records available for inspection;  Maintaining a record of accreditation for all laboratories used during the trial.

PIs must be active staff members (non-trainees) of the DF/HCC. The PI assumes responsibility for the overall review and conduct of the research across the DF/HCC. In addition to the overall PI, a Site PI must be designated for each institution for trials conducted across the DF/HCC.

The regulations require that the IRB have a policy for responding to serious and continuing noncompliance. The IRB and the institutions take these issues very seriously. It is imperative that investigators understand their role and responsibilities.

32.2 Financial Disclosure by Clinical Investigators Please see the Section on Conflict of Interest Policy for relevant policies and the review practices. The DFCI IRB requires all research staff to indicate, at the time a protocol is submitted for review, if they, their spouse or dependent children have any financial interests that might be affected by the research, or in entities whose financial interest might be affected by the research. If so, the research staff member must indicate the nature of the financial interest (e.g. income, equity, rights in intellectual property, etc), and the value of the interest. Potential Conflicts of Interest are reviewed as described in the next section.

32.3 CONFLICT OF INTEREST POLICY

There are two policies that the DF/HCC applies to identify and address Investigators’ potential conflicts of interest in Human Subject Research: the HMS Interim Policy Statement on Conflicts of Interest and Commitment (“HMS Policy”, and PHS Regulation 45 CFR Part 50, subpart F, “Responsibility of Applicants for

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Promoting Objectivity in Research for which PHS Funding is Sought” (“PHS Regulation”). These policies apply to all research activities, including research involving human subjects that is subject to review by the DFCI IRB, acting on behalf of DF/HCC. In addition, each Investigator participating in DF/HCC research project involving human participants must abide by the Conflict of Interest policy of his/her primary institution, and when applicable, by FDA Regulation 21 CFR Part 54 “Financial Disclosure by Clinical Investigators” for investigational drug, biologic and device studies.

HMS Policy Under the HMS Policy, Investigators must disclose all Financial Interests in outside entities, including those held by a spouse, domestic partner, and children (“Family”). Investigators who have certain Financial Interests may not participate in human subject research except under specific de minimis exceptions:

 Investigators and their Family may not receive Income from a Business whose Technology is being investigated in human subjects (or it’s agent or representative), unless: o The income does not exceed $10,000 annually; o The income exceeds $10,000 annually but is obtained as the result of the career pursuits of the Investigator’s spouse or domestic partner. This exception is allowable only after review and approval by the relevant Conflict of Interest Committee(s), and may require the implementation of a management plan to protect human subjects and ensure the integrity of the research. o The income is received as the result of the Institution’s technology licensing activities, and is either: . is the result of payments for post-market royalties; or . has been reviewed and approved by the relevant Conflict of Interest Committee(s).

 Investigators and their Family may not hold equity in a Business whose Technology is being investigated, unless: o the Business is publicly held, and o the value of the equity interest does not exceed $30,000 at any given time, and o the equity was not obtained in connection with the human subject research at issue (for example, the equity was inherited, or was obtained before the Investigator developed a research relationship with the business). For the purpose of this rule, “equity” includes any ownership in the Business (e.g. stock, stock options, or in any other form) but excludes ownership of a mutual fund, pension, or other institutional investment fund over which the participant does not exercise control.

Other institutional revenue may be excluded after review by the HMS Standing Committee on Conflicts of Interest.

PHS Regulations According to the PHS Regulation, Investigators in research supported by PHS funding must disclose all Significant Financial Interests (“SFI”) to his or her Institution. An interest is “significant” if it is:  For a publicly traded entity: Income or remuneration, and/or equity (or any combination thereof) received in the previous 12 months with a value that exceeds $5,000 in the aggregate at the time of disclosure;

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 For a non-publicly traded entity: Income or remuneration received in the previous 12 months with a value exceeding $5,000 in the aggregate at the time of disclosure, or any equity in the entity;  Intellectual property rights and interests (e.g., patents, copyrights) upon receipt of income related to such rights and interests;  Any travel that is reimbursed (i.e., the Investigator is made whole for the financial outlay required) or sponsored (i.e., the costs are paid on behalf of the Investigator such that the exact monetary value may not be readily available) with an aggregate value of $5,000 per entity. Travel that is sponsored or reimbursed by any of the following need not be disclosed: o the Investigator’s primary institution, o any Federal, state, or local government agency, o Institutions of higher education, academic teaching hospitals, medical centers, or their affiliated research institutions.

The Institution must review Investigator SFI disclosures and, through its Designated Official, reasonably determine whether the significant financial interest is related to the research in that the financial interest could affect, or is in any entity whose financial interest could be affected by, the research; if so, the Institution must reasonably determine whether the interest could directly and significantly affect the design, conduct or reporting of the proposed research (and therefore constitute a financial conflict of interest). The Institution is tasked with the obligation of determining how to manage all financial conflicts of interest. If so, a Conflict of Interest is determined to be present, the Institution must implement a management plan that is sufficient to safeguard the integrity of the research. The existence of an FCOI, along with the specifics of the applicable management plan, must be reported to PHS.

Institutional Review and Oversight

Each participant (member of the study team or “Participant”) in the clinical trial must indicate in the Statement of Investigator Form all Financial Interests in the Business that is sponsoring the study or that owns or has licensed the Technology under study. If the Participant indicates that he/she has such a Financial Interest, he/she must indicate the value. The absence of Financial Interest must be positively noted on the Statement of Investigator Form.

When a Financial Interest is reported that requires institutional review, the DFCI Faculty Committee on Conflicts of Interest will review the circumstances of the financial interest and the research and make recommendation with respect to the management. If the submitting institution is is anything other than DFCI, the management plan is submitted for review by the COI committee of that institution which can then impose stricter requirements but may not impose less strict requirements for management.

Investigators have an on-going obligation to comply with the requirements of an imposed management plan until the completion of the research, or until such time as the Institution determines that the management plan is no longer required. Compliance with any management plan shall be reviewed by the DFCI IRB as necessary.

Review of Outside Interests

A. Income from Outside Activities:

For the purposes of this section, “income” includes:

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 compensation for services (e.g. consulting, SAB participation);  income from rights to intellectual property received from an entity other than a current DF/HCC academic appointment (see Section 4)  for the purposes of PHS-funded research, travel sponsored or reimbursed by a Business may be reviewable

(1) Income received/ expected is less than$5,000:

No further action is required by DFCI/HMS policy or PHS regulations; however, the DFCI COI Committee may review the potential for COI in certain circumstances (e.g. where the study is particularly high risk, or upon request from the IRB), and may make whatever determination it deems appropriate under the specific circumstances, including a determination that any COI is unmanageable. In addition, the IRB must determine whether or not patients need to be informed of this financial interest in the consent document.

(2) Income received/expected is greather than $5,000:

a. If research is not subject to PHS regulations: No further review is required by the DFCI/HMS policy unless the interest exceeds $10,000, in which case DFCI/HMS policy prohibits an Investigator from participating in human subjects research on technology owned by, or obligated to, a business from which s/he has received in excess of $10,000 in income in the previous 12 months.

b. If research is subject to PHS regulations1: DFCI is required to determine if the financial interest is related to the research, and if so, whether it is reasonable to conclude that it could directly and significantly affect the design, conduct or reporting of the research. If so, the DFCI COI Committee will determine whether a management plan can be implemented to safeguard the integrity of the research, and shall provide a copy of any management plan to the IRB. If the research involves investigators from non-DFCI affiliated institutions, DFCI shall provide a copy of the plan to the relevant institution for review and approval; DFCI will accept changes to the plan that impose stricter management.

B. Equity in a Publicly Traded Business:

1. Value of equity is less than $30,000: allowable according to HMS Policy and subject to review under the PHS Regulations.

2. If the value of the equity is greater than $30,000 OR exceeds 5% ownership of the Business, OR the equity was acquired such that it might appear to be related to the research, participation in the research is prohibited by DFCI/HMS policy. The Investigator may not participate in the research until his or her equity ownership is within the allowable ranges, and in compliance with any resulting required management plan.

C. Equity in a Privately Held Business:

1. Any amount (zero threshold) is subject to review and management by DFCI COI Committee. However, Investigators may not participate in Clinical Research on any technology owned by or obligated to the non-publicly traded entity in which s/he has an equity interest. The Investigator must divest his or her prohibited equity interest prior to participation in the clinical research.

1 Research is subject to PHS regulations if it is funded, in whole or in part, by a PHS agency (e.g. NIH) or by a sponsor specifically adopting the PHS policy on Conflicts of Interest (e.g. Komen for the Cure, American Cancer Society).

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D. Income from Rights to Intellectual Property from Investigator’s Current Institution

1. All income received as a result of institutional technology licensing from an Investigator’s current institution is excluded from review by the PHS regulations.

2. Income received as a result of institutional distribution of post market royalties in accordance with its technology licensing activities is specifically excluded from review under DFCI/HMS policy. Income received as a result of institutional distribution of payments related to premarket technology are considered “income” as outlined in Section A, but may be excluded after review and approval by DFCI COI Committee and HMS Standing Committee on Conflicts of Interest.

Role of the IRB

Whenever IO/COI Committee review is required, the DFCI IRB will be notified of the need for review of the outcome of the committee’s review and a copy of the management plan if deemed necessary.

The IRB will then determine whether it concurs with the recommended assessment of the conflict, and the appropriateness of the management plan to assure objective oversight of the clinical trial. The IRB may concur with the recommendations, or may choose not to accept the management plan, instead determining that the financial interest could jeopardize the objectivity of the study.

If the IRB approves the plan for management of the conflict, then the IRB should determine what information should be disclosed to the participant and determine the appropriate language for disclosure of this financial interest to study subjects in the consent document.

If the study team includes an investigator with a potential conflict of interest who is not the PI, the protocol may be approved without the participation of that study team member (unless that individual is critical to the performance of the study). If the protocol has been submitted before the conflict of interest review process has been completed, the investigator may not participate in the study until all required levels of review have been completed and any plan for management and disclosure of the conflict receives concurrence by the IRB. Upon completion of the appropriate levels of review, with concurrence of the IRB, the investigator may be added to the protocol via an amendment.

If the PI has a financial interest that is not acceptable to the IRB for any reason, the trial cannot be approved until the financial interest is: 1. Reduced or eliminated; 2. A more stringent management plan is submitted; or 3. Alternatively, another PI is named.

Definitions

Business: Any legal entity organized for profit or non-profit purposes.  This term includes, but is not limited to: corporations, partnerships, sole proprietorships, associations, organizations, holding companies, and business or real estate trusts.  A Business is considered to be “non-profit” if it is legally organized for charitable purposes (e.g., 501(c)(3) and equivalents), unless it is principally organized, funded and/or managed by one or more for- profit entities engaged in commercial or research activities of a biomedical nature.

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 Dana-Farber Cancer Institute is not considered a “business” for the purpose of this policy.

Clinical Research: Any research that involves interventions in human subjects or their identifiable specimens and that is not “Nominal Risk Clinical Research” as determined by the Institutional Review Board and/or conflict of interest committee of DFCI or one of its affiliated institutions.

Covered Person: A member of the DFCI faculty or research staff.

Nominal Risk Clinical Research. This includes Clinical Research that is:  Minimal risk (as that term is defined in 45 CFR Part 46) and  Falls within one or more of the following categories: o Use of bodily fluids, secretions or other biospecimens (excluding such materials obtained for clinical care purposes, which are covered in b, below) that are obtained through non-invasive, routine and established collection procedures from a healthy, non-pregnant individual who is not a member of a vulnerable population (as defined in 45 CFR part 46) and provided that the samples cannot be linked to any individually identifiable person by any Faculty member who participates in the Nominal Risk Research; o Use of excess bodily fluids, secretions or other biospecimens, which may be linked by a Faculty member who participates in the Nominal risk Research to an individually identifiable patient, where the samples are otherwise obtained during the course of clinical care by an individual who (1) does not participate in the Nominal Risk Clinical Research; (2) is not under the direction or control of any individual who participates in the Nominal Risk Clinical Research; and (3) is not supervising any individual who participates in the Nominal Clinical Risk Research; o Medical records review, including collection of coded identifiable data, provided, however, that the protocol ensures that, after collection of the data, any Faculty who participate in the Nominal Risk Research cannot link it to an individually identifiable patient.  Non-sensitive survey research on individuals or group characteristics or behavior, provided that if the subjects are considered members of a vulnerable population (as defined by 45 CFR Part 46), the institution’s conflicts of interest committee and/or Institutional Review Board may, on a case by case basis, conclude that the research is not Nominal Risk Clinical Research; or  Such other categories of research activities, as may from time to time, be so designated by the DFCI Faculty Conflict of Interest Committee.

Family: The “Family” of a Faculty member includes his or her spouse or domestic partner, and dependent children.

Financial Interest: Any equity interest in a Business (“Equity Financial Interest”) or the receipt of, or the right or expectation to receive (except rights to future income under institutional royalty sharing agreements), any income from a Business (“Income Financial Interest”).  Equity Financial Interests may include any type of ownership interest, such as owning stock or stock options, but excludes equity that arises solely by reason of investment in a Business by a mutual, pension, or other institutional investment fund over which the Faculty member does not exercise control.  Income Financial Interests may take the form of various types of compensation and may be paid either by the Business or by an agent or other representative of the Business on its behalf. Examples of income that might be paid or owed by a Business to a Faculty member include, but are not limited to, consulting fees, salary, or other payments for various services, interests in real or personal property, divi- dend payments, payments derived from the licensing of Technology, and forgiveness of debt. The term explicitly excludes, however, Post-market Royalties.

Participate: To be responsible for the design, conduct, or reporting of research, regardless of title or position.  This term includes, but is not limited to, those individuals who serve as principal investigator, co- investigator, study designer, research collaborator, provider of direct patient care in connection with the study, or author on a publication of the study.

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 This term assumes that the individual may have the opportunity to influence or impact the results. It is not intended to apply to individuals who provide primarily technical support to a research study or who act in a purely advisory capacity with no direct access to the study data, unless such individuals are nonetheless in a position to influence or impact the study’s results or have privileged information as to its outcome.  If a Faculty member participates in research pursuant to this definition, such participation shall be considered to apply to all aspects of the research study (one cannot claim to participate in some, but not all, aspects of research) and for the entire duration of the study (one cannot elect to terminate participation prior to the end of the study).

Personal Gifts: Anything of value that is received by an individual for which the recipient has not paid fair market value.

Post-market Royalties: Royalties received by a Faculty member directly or under an institutional royalty sharing agreement as a result of the sale of a Technology invented by the Faculty member in the public market (e.g., if applicable, post FDA-approval). This term does not include license fees, annual maintenance fees, milestone payments or other income that may become due under a license prior to market approval of the Technology.

Research: A systematic investigation designed to develop or contribute to generalizable knowledge relating broadly to public health, including behavioral and social sciences research. The term encompasses basic and Clinical Research, including applied research and product development.

Sponsored Research: Research, training and instructional projects involving funds, personnel, certain proprietary materials, or other compensation from outside sources under an agreement that (i) the institution classifies as a sponsored award in accordance with institutional policyi or (ii) gives the donor, or an identifiable third party designated by the donor, preferred access to or ownership rights over the research or the products of the research, e.g. raw data, scientific developments or intellectual property. Provision of periodic general reports and copies of publications shall not be considered preferred access. Notwithstanding the forgoing, the term “Sponsored Research” shall not incorporate the following agreements:  Gifts: Agreements that an institution classifies as a gift in accordance with institutional policy except as specifically set forth below: o Faculty Members who hold equity in the donor company are prohibited from receiving gifts that are made solely for the support of the Faculty Member’s research or that of the Faculty Mem- ber’s laboratory.  Certain Material Transfer Agreements: Agreements that provide for the provision of tangible materials, including equipment(“Material”) from an outside source pursuant to a material transfer or other agreement provided each of the following factors are met: o The proposed protocol does not consist of research on the material in question, either directly or indirectly (e.g., the primary usefulness of the material in the proposed protocol is as a research tool to achieve scientific aims distinct from the donor company’s business aims and not as a potential product or integral component of such product); o The proposed agreement does not grant to the business any rights to intellectual or tangible property created in, or resulting from, the use of the material in the proposed research, except: . Options to negotiate (even if such options are exclusive) a license to intellectual property made in, and derived directly from, the use of the Material in the Research; or . A non-exclusive license for research purposes to intellectual property made in, and derived directly from, the use of the Material in the Research. o The agreement otherwise meets with the approval of designated University/Hospital institutional officials, who may impose additional prohibitions and/or restrictions in view of potential conflicts, as deemed warranted.

Technology: Any compound, drug, device, diagnostic, medical or surgical procedure intended for use in health care or health care delivery. A Technology “belongs” to a business in a way that would implicate the

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Research Rules in this policy if the business (i) manufactures the Technology; (ii) has or is seeking licensing rights to the Technology; or (iii) has any other financial stake in the Technology such that the success or fail- ure of it as a commercial venture will impact the business.

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Section 33 - Study Coordinators

33.1 Roles and Responsibilities

The study coordinator position may also be referred to as “CRC”, “CRA” or “data manager.” The study coordinator is an integral part of the study team and works closely with the overall PI, the research nurse, and the ODQ data analyst. This section will provide an overview of the roles and responsibilities of a study coordinator. The specific roles and responsibilities may vary by institution. Please consult your supervisor for an institution-specific job description.

33.2 Protocol Management

These topics summarize the responsibilities involved in managing protocols.

Understanding the Protocol Document

The study coordinator should possess a complete understanding of the following protocol elements essential to running a trial and ensuring protocol compliance: . Trial objectives . Eligibility criteria and enrollment procedures . Treatment procedures . AE reporting . Measurement of trial outcomes . Trial parameters (required tests and procedures) . Drug formulation and procurement, if applicable . Research samples (pharmacokinetics, blood, tissue, etc.) . Required data/records to be maintained . HIPAA requirements and data security

Subject Enrollment

Often, the study coordinator plays a major role in the enrollment of clinical trial participants. The following are procedures that must be followed to ensure that only those participants who meet the eligibility criteria are enrolled:

 Screening: Procedures that are to be performed as part of the practice of medicine and that would be done whether or not trial entry was contemplated, such as for diagnosis or treatment of a disease or medical condition, may be performed and the results subsequently used for determining trial eligibility without first obtaining consent. Informed consent must be obtained prior to initiation of any clinical screening procedures that are performed solely for the purpose of determining eligibility for research. A HIPAA waiver must be approved by the IRB prior to review of clinic lists or the LMR.

 Informed Consent: Confirm the most current version of the informed consent document is being used. The expiration date is located on the footer of every informed consent document. Each time a new participant is to be consented, the consent form must be printed from OncPro.

 Eligibility: Verify the potential participant’s eligibility by reviewing the criteria outlined in the IRB approved protocol. Confirm that all required tests and screening have been performed. Eligibility checklists are posted on OncPro with other trial-related materials. Refer to the protocol eligibility

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checklist documents required by the sponsor/cooperative group. Refer to the protocol document for specific instructions for additional registration or enrollment procedures.

 Registration: Once a participant is determined to be eligible for enrollment, registration must be completed with the ODQ and the sponsor or any cooperative group, if applicable, prior to the participant beginning study treatment.

Study coordinators for non-clinical trials should follow the procedures outlined above, as they apply to the type of research being undertaken. Coordinators must be familiar with the ODQ registration requirements and when they are applicable to non-clinical research. In studies where the IRB has determined that coordinators may obtain informed consent from participants, coordinators must be familiar with the consent process.

33.3 Data Management

These topics describe some of the documents and procedures involved in data management.

Source Documents

The information captured in source documentation is extracted and transcribed onto the trial’s case report forms (CRFs). It generally falls to the study coordinator to collect and manage this data collection and abstraction. The study coordinator is responsible for submitting the data in a timely fashion.

The International Conference on Harmonization (ICH) guidelines define source documentation as “original documents, data, and records (e.g., hospital records, clinical and office charts, laboratory notes, memoranda, subject’s diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions certified after verification as being accurate copies, microfiches, photographic negatives, microfilm or magnetic media, X rays, subject files, and records kept at the pharmacy, at the laboratories and at medico-technical departments involved in the clinical trial).” (Source: ICH GCP Guideline 1.52)

Case Report Forms (CRFs)

CRFs (electronic or paper) capture all research data necessary to assess the outcomes in clinical trials. CRFs for each participant enrolled in the trial are completed, maintained, and then submitted to the sponsor throughout the trial at intervals specified in the protocol document. All data transcribed onto the CRF must correspond accurately with the source documentation. Discrepancies will be scrutinized and clarification sought through a query process.

The design of the CRFs depends on the trial’s sponsor. The CTRIO designs CRFs for PI-initiated, in- house trials. In these cases, all original CRFs should be submitted to the assigned data analyst at the ODQ for each participant. Sponsors, such as pharmaceutical companies and cooperative groups create CRFs for trials being conducted at DF/HCC, and data for these trials will be submitted as outlined in the protocol document.

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Errors are sometimes identified on CRFs. Corrections on electronic CRFs should be made according to the sponsor’s guidelines. When corrections need to be made to a paper CRF, draw a single line through the error and write the correct value next to the error. Do not obscure the original entry. Each correction must be initialed and dated. If the CRF was already submitted and the error is found and corrected later, please make the correction to the copy of the CRF, write “correction” at the top of the CRF with the correction highlighted, and resubmit the CRF to the appropriate office. Whiteout must never be used on a CRF or any other medical record.

Query Resolution

All trials typically are monitored and/or audited. Often a trial sponsor may send a monitor to review their data. The auditing team in the ODQ also performs this function. There may be discrepancies between the CRFs and the source documents requiring clarification or correction. This is called the “query resolution process.”

Adverse Event (AE) Reporting

AEs experienced by trial participants must be reported promptly to the IRB and appropriate federal, state, and sponsoring agencies. Guidelines for AE reporting are typically outlined in the protocol document. Sponsors/cooperative groups will also have their own standards for AE reporting that may differ from the DFCI IRB policy. All reporting requirements must be met.

The study coordinator may be delegated responsibility for drafting the report, which is then reviewed and signed by the reporting investigator. The final AE report is then submitted to the IRB and other relevant groups.

For the DFCI IRB specific reporting requirements, see the Adverse Event (AE) Reporting Policy section of this guide.

Research Files

Research files contain copies of source documentation for each participant.

Study Diaries and Questionnaires

As part of the protocol activities, the participant may be required to record drug administration or other trial experiences in a study diary. Participants may also be asked to complete a questionnaire while on trial. A study coordinator may be responsible for administering the study questionnaires at the proper times specified by protocol and retrieving these materials for documentation purposes.

33.4 Drug Accountability

The study monitor performs drug accountability. This is done at the time of the monitoring visit with the investigational pharmacist. A study coordinator may be responsible for scheduling visits with pharmacy staff.

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33.5 Regulatory Submissions

The study coordinator assists the PI with correspondence to regulatory agencies, such as the IRB, and/or the sponsor/cooperative group to ensure that all regulatory requirements have been met. Please refer to Protocol Submission, Review, and Activation section of this Guide for a list of the basic elements of an IRB submission. The study coordinator may be responsible for completing these forms on behalf of the PI:

 New Submissions: The study coordinator may assist the PI in preparing the new protocol submission and managing any conditions for approval and/or activation.  Continuing Reviews: Regulations mandate that research trials must be reviewed by the IRB at least once per year in order for the research to continue. The study coordinator may assist the PI in preparing the continuing review for submission to the IRB. The study coordinator will also maintain and submit a Minor Deviation/Violation Log to the IRB at least annually with the continuing review submission.  Amendments: During the course of a trial, components of the research may be revised. Such changes may require SRC review and will require IRB review and approval prior to initiation. Activation may also be required. The study coordinator may oversee this process as well.  Major Deviations/Violations/Exceptions: Deviations, violations and exceptions that meet the DFCI IRB reporting policy of a Major event must be reported to the DFCI IRB as such. The study coordinator may be responsible for gathering the appropriate information, sponsor approval and completing the forms.  Unanticipated Problems Involving Risks to Subjects or Others: Events that meet the reporting criteria outlined in the DFCI IRB Unanticipated Problem Reporting Form must be reported to the DFCI IRB as such. The study coordinator may assist the PI in completing the UAP report.

33.6 The Regulatory Binder

The study coordinator is responsible for maintaining the regulatory binder, which includes documentation of everything that has happened to a particular trial from the time of submission to completion. Generally, the sponsor of an industry-sponsored trial will provide binders to house study-specific regulatory documents. Sections within a regulatory binder may include, but are not limited to:

 IRB Submission Track Sheet: All items sent to the IRB for review and the subsequent approval dates should be listed and initialed on this sheet.  IRB Initial Approval: This section includes the IRB application, all IRB correspondence pertaining to the initial approval of the trial, any responses submitted by the PI, and the IRB approval and activation memos. Radiation and/or biosafety committee correspondence, NCI approvals, and pathology committee correspondence and approvals also are included within this section.  IRB Continuing Reports: This includes the continuing review report, any relevant IRB correspondence, and the IRB continuing review approval memo.  IRB Amendment Approvals: Copies of all amendment forms, IRB review memos, and IRB approvals are incorporated in this section.  Pharmacy Correspondence: Any pharmacy-related correspondence is included in this section.  Other Committee Correspondence (if applicable): Copies of any violation/deviation forms and exception requests are incorporated here.

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 Legal/administrative (if applicable): This section includes any documentation relating to the budget, contract with the sponsor, and FDA forms (1571 and 1572).  General Correspondence: This section includes any correspondence among the study team and between the study team and other departments relating to the trial.  AE Reports: All AE and IND/IDE safety reports, IRB responses, and any other relevant correspondence are included in this section.  Master Protocol: The current versions of the protocol and consent documents are located in this section.

ODQ audit reports should be filed separately, not in the regulatory binder. See the Monitoring and Audit Preparation section below. Non-clinical research teams should also maintain a research binder that includes the necessary study documents as outlined above, as applicable.

33.7 Research Sampling

Many trials involve the procurement of research samples from trial participants. Examples of research samples are tissue, urine, and blood.

In terms of sample collection, the study coordinator may be responsible for making sure that: . Samples are drawn at the times specified by the protocol . The correct tubes are used by phlebotomy/nursing . All samples are labeled properly and the correct paperwork is completed . Samples are stored at correct temperature or sent out to the proper recipients

Refer to the protocol for a list of specific sample collection requirements and procedures.

33.8 Monitoring and Audit Preparation

During the life of a trial, routine monitoring and auditing visits should be expected. Depending on the type of trial, the types of monitoring visits and audits will vary. However, their intent is the same – to ensure the best and most accurate data are being collected.

Sponsors representatives will visit a research site on a regular basis to monitor the trial progress or perform an audit of the trial. The sponsor may also send an independent firm to perform a quality assurance (QA) audit.

Federal regulatory agencies, such as the FDA and the NCI also may audit the research site, the investigator, or the research trial.

The ODQ also audits trials conducted within DF/HCC. The ODQ audits ongoing trials, including in- house trials, each year on a random basis. For sponsored trials, a study coordinator acts as a liaison between the PI and the pharmaceutical company, CRO, or cooperative group.

The study coordinator may be responsible for:

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 Coordinating visits with the sponsor/cooperative group and other DF/HCC sites, if applicable;  Coordinating times for the PI to meet with trial representatives;  Ensuring CRFs are completed;  Making medical records readily available;  Resolving previous follow-up issues;  Coordinating pharmacy monitoring visits;  Updating regulatory files.

Important things to keep in mind during the monitoring visit: 1. Do not make any changes to AE pages (especially the relationship section) without discussing with PI; 2. Do not allow monitors to make photocopies of medical records; 3. If you are uncertain about something, refer it to the PI or your manager.

33.9 Checklist for Monitoring and Auditing Visit

The ODQ has a checklist to help a study coordinator prepare for a monitoring or auditing visit. (Refer to Appendix A of the Clinical Trials Audit Manual This checklist is suitable for visits performed by internal as well as external monitors and auditors.

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Section 34 - Investigator-held INDs

A trial sponsor may be a drug company/manufacturer or a single investigator. When an investigator holds his or her own IND, the FDA considers the investigator to be a sponsor-investigator. This means that one individual is assuming all of the responsibilities of the study sponsor in addition to that of the overall principal investigator. The sponsor-investigator should be aware of all the Federal Regulations that address these responsibilities. Many of the regulations can be found in 21CFR 312 Sections 20 through 70. The DF/HCC also has an SOP document that specifically outlines these responsibilities RCO-100.

The additional responsibilities of a sponsor include:  All of the regulatory reporting (FDA) requirements;  Responsibility for drug manufacturing and control issues, including proper labeling of the investigational product;  The assessment of safety;  Ensuring IRB approval prior to shipping clinical supplies to sites;  Communicating with and monitoring all participating investigators.

34.1 IND Overview

Before conducting a clinical trial with an investigational new drug (IND), the sponsor-investigator must submit an IND application to the FDA. The FDA reviews the application for both subject safety and the ability to satisfy the requirement for efficacy. FDA has 30 days from date of receipt of an IND to make a determination on whether it is safe for the sponsor-investigator to proceed. If no notice is received within the 30-day period, the IND is considered approved. The sponsor-investigator should confirm that the FDA did, in fact, receive the application and that they do not have any issues or concerns with the application prior to enrolling participants to the trial.

In some cases it may not obvious that an IND is required for a proposed trial. DF/HCC strongly encourages the sponsor- investigator to request the FDA’s assistance in making the determination. If it a much safer path for the sponsor-investigator to file an IND application and have it deemed exempt than not to file and later be subject to a determination that an IND should have been requested. It is recommended that the sponsor- investigator be a practicing physician and that the trial be submitted sequentially for review to the FDA and IRB, unless IRB approval is necessary to secure funding. Individual institution Clinical Trials Offices may offer additional assistance in preparing IND applications. (DFCI CTO, MGH CCPO, or BIDMC CCTO).

In preparing and maintaining an IND application, sponsor-investigators may find the following documents developed by DF/HCC useful in the initial submission of the IND application and in the submission of periodic reports to the FDA.

 Biomedical Protocol Template  Original IND Submission Transmittal Letter  Original IND Application Template  IND Amendment Transmittal Letter  IND Safety Reporting Transmittal Letter  IND Annual Report Transmittal Letter

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 IND Annual Progress Report  IND Withdrawal Transmittal Letter

These documents are available through the DF/HCC Clinical Investigator Toolkit on the DF/HCC website.

34.2 General Principles of the IND Submission 21 CFR 312.22

The FDA’s primary objectives in reviewing an IND are, in all phases of the investigation, to ensure the safety and rights of participants. In Phase II and Phase III trials, the FDA helps to ensure that the quality of the scientific evaluation of drugs is adequate to permit an evaluation of the drug’s effectiveness and safety. Therefore, although the FDA’s review of Phase I submissions will focus on assessing the safety of Phase 1 investigations, the FDA’s review of Phases II and Phase III submissions will also include an assessment of the scientific quality of the clinical investigations and the likelihood that the investigations will yield data capable of meeting statutory standards for marketing approval.

The amount of information on a particular drug that must be submitted in an IND depends upon such factors as the novelty of the drug, the extent to which it has been studied previously, the known or suspected risks, and the developmental phase of the drug. The central focus of the initial IND submission should be on the general investigational plan and the protocols for specific human trials. Subsequent amendments to the IND that contain new or revised protocols should build logically on previous submissions and should be supported by additional information, including the results of animal toxicology trials or other human trials as appropriate. Annual reports to the IND should serve as the focus for reporting the status of trials being conducted under the IND and should update the general investigational plan for the coming year.

34.3 IND Content and Format 21 CFR 312.23

The IND format is described in the regulations in 21 CFR 312.23 and should be followed by the sponsor- investigator in the interest of fostering an efficient review of applications. The general format is described below. The investigator is expected to exercise considerable discretion, however, regarding the content of information submitted in each section, depending upon the kind of drug being studied and the nature of the available information.

Note: An investigator who uses, as a research tool, an IND that is already subject to a manufacturer’s IND or marketing application should follow the same general format but ordinarily may, if authorized by the manufacturer, refer to the manufacturer’s IND or marketing application in providing the technical information supporting the proposed clinical investigation. The investigator should include in the IND application a copy of the Letter of Authorization (or Cross-Reference Letter) from the manufacturer which allows the reference to the manufacturer IND. An investigator who uses an investigational drug not subject to a manufacturer’s IND or marketing application is ordinarily required to submit all technical information supporting the IND, unless such information may be referenced from the scientific literature.

The necessary documents needed to compile an IND include: 1. A cover letter; 2. FDA form 1571: The Investigational New Drug Application Form; 3. FDA form 1572: The Statement of Investigator Form; 4. A table of contents; 5. An introductory statement or background information intended to place the development plan for the drug into perspective and help the FDA understand that study hypothesis;

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6. A general investigational plan describing the general steps that will be carried out in order to perform the study; 7. An investigator’s brochure, if required under 21 CFR 312.55; 8. The study protocol(s) describing the methodology to be used and an analysis of the protocol demonstrating its scientific soundness; 9. The informed consent document explaining the study, procedures, risks, benefits, alternative treatment, compensation and confidentiality measures; 10. Chemistry, manufacturing, and control data sufficient to assure the proper identification, quality, purity, and strength of the investigational drug. If the drug is legally marketed in the U.S., this should be stated; 11. Investigational drug labeling with a warning stating “caution new drug for investigational use only.”; 12. Environmental assessment indicating whether or not the research or study will affect the environment. For more information, refer to a claim for categorical exclusion under 21 CFR 25.30 or 21 CFR 25.31 or an environmental assessment under 21 CFR 25.40; 13. Pharmacology and toxicology data that describes the mechanism of action of the drug, its toxicological effect and its pharmacological effects (absorption, distribution, metabolism and excretion) in animal and in vitro; 14. Previous human experience with the investigational drug; 15. Articles cited in the study protocol; 16. A Letter of Authorization (or Cross-Reference Letter) if provided by the Manufacturer to reference the Manufacturer’s IND for the investigational product.

34.4 Submission of the IND application to the FDA

IND applications are submitted to one of two centers within the FDA, the Center for Biologics Evaluation and Research (CBER) or the Center for Drug Evaluation and Research (CDER). The decision governing which center is appropriate is dependent on the nature of the experimental agent described in the IND. Generally, the CBER oversees vaccine and blood-related products, while the CDER has oversight responsibilities for drugs and biologics. Questions about the appropriate center for submission can be directed to the:

 CBER Ombudsman at (301) 827-0379 or [email protected]  CDER Ombudsman at (301) 796-3436 or [email protected]

General Submission Information I. If the sponsor-investigation involves an exception from informed consent under 21 CFR 50.24, the sponsor-investigator should prominently identify in the cover letter that the investigation is subject to the requirements in 21 CFR 50.24 of the regulations. II. The submission must be broken down into volumes, each page paginated (numbering of each page in sequence in the submission, regardless of the page number already on it). III. The original IND and all subsequent amendments must be submitted in triplicate (one original and two copies, per 21 CFR 312.23). Processing may be delayed if insufficient copies are submitted. IV. Typically each submission relating to an IND should be numbered serially. The initial IND is numbered 0000; each subsequent submission (e.g., amendment, report, correspondence) is numbered chronologically.

Submissions should be sent to the appropriate division within the FDA as outlined below.

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Biologics Center for Drug Evaluation and Research (CDER)

Drugs Center for Drug Evaluation and Research (CDER)

Vaccines/gene therapy Center for Biologics Evaluation and Research (CBER)

34.5 IND Application Approval Process

FDA will respond within 30 days with an acknowledgment letter and an IND number.

Note: This means the IND has been successfully filed, however, the research cannot begin until 30 days after the IND has been received by the FDA, unless earlier notification by FDA is received stating that the research may begin. After the acknowledgment the FDA may respond in one of two ways.

1. The FDA may request additional information and may place clinical holds on the research. The research cannot begin until all concerns raised by the FDA have been responded to their satisfaction; 2. The FDA may conclude that the research is exempt. An exemption means that the research may be conducted without filing an IND application or subsequent information to the FDA.

Note: An IND exemption does not release a sponsor-investigator from his/her submission and/or reporting requirements to the IRB.

34.6 IND Post-Approval

After approval of an IND, the sponsor-investigator is subject to conditions set forth by the FDA. The following sections outline these conditions and the responsibilities of an IND sponsor-investigator.

34.7 IND Protocol Amendments 21 CFR 312.30

If any change is made to the research protocol, the amendment must be submitted to FDA to ensure that the clinical investigations are conducted according to protocol included in the application. Changes include: . New protocol(s) under an existing IND . Changes to the existing protocol(s) . Addition of a new investigator to an existing protocol

New Protocol(s) A new protocol may begin only after the IND protocol amendment has been submitted to the FDA for review and the protocol has been approved by the IRB of record.

Changes in Existing Protocols A sponsor-investigator should submit a protocol amendment for any change that significantly affects the safety of participants, or any change in a Phase 2 or 3 protocol that significantly affects the safety of participants, the scope of the investigation, or the scientific quality of the study as outlined in 21 CFR 312.30.

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Protocol changes are made only after the protocol amendment has been submitted to the FDA for review and the protocol amendment has been approved by the IRB.

New investigator A protocol amendment should be submitted when a new investigator is added to a previously submitted protocol. An amendment is not required when a licensed practitioner is added to a treatment (single- patient IND) protocol per 21 CFR 312.30.

Once added to the study the new investigator may receive shipments of investigational drug and may begin participating in the study. The overall PI should submit the protocol amendment to report the addition of a new investigator within 30 days of the addition.

Content and Format of an IND Protocol Amendment The specific purpose of the protocol amendment should be prominently identified (i.e., Protocol Amendment: New Protocol, Protocol Amendment: Change in Protocol, Protocol Amendment: New Investigator), and include the following: 1. New protocol: A copy of the new protocol along with a brief description of the most clinically significant differences between it and the previous protocol(s); 2. Protocol Change: A brief description of the change and reference (i.e., date and number) to the submission that contained the protocol; 3. New Investigator: The investigator’s name and address, qualifications to conduct the investigation (i.e., CV), the name and address of the research facility used by the investigator, the name of each co-investigator (i.e., fellow, resident, etc.) working under the supervision of the investigator; the name and address of the investigator’s IRB, and a reference (i.e., date and number) to the submission containing the previously submitted protocol to which the investigator is being added; 4. Reference: Identify specific information either in the existing IND or in a concurrently submitted IND amendment that is necessary to support any clinically significant change. References to existing INDs include the reference number, volume number, and page number of the specific information being referenced.

34.8 IND Safety Reports for Investigator-Held INDs 21 CFR 312.32

The sponsor-investigator is responsible for submitting safety reports to the FDA. This section describes the FDA’s expectations. The sponsor-investigator should be aware that IRB requirements are slightly different than FDA requirements. The sponsor-investigator is responsible for being familiar with and meeting expectations of both sets of requirements. Additionally, if the trial involves recombinant DNA, there may be additional reporting requirements to the OBA and/or the NIH and/or the OHRP. The sponsor-investigator is responsible for being familiar with these requirements as well as meeting these requirements.

Definitions: Associated with the use of the drug: There is a reasonable possibility that the experience may have been caused by the drug.

Disability: A substantial disruption of a person’s ability to perform normal life functions.

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Life-threatening adverse drug experience: Any adverse drug experience that places the participant 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).

Serious adverse drug experience: 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, a 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 hospitalization may be considered a serious adverse drug experience when, based upon appropriate medical judgment, they may jeopardize the participant and may require medical or surgical intervention to prevent one of the outcomes listed in this definition.  Examples of such medical events include allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of drug dependency or drug abuse.

Unexpected adverse drug experience: 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.  For example, under this definition, hepatic necrosis would be unexpected (by virtue of greater severity) if the investigator brochure only referred to elevated hepatic enzymes or hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis would be unexpected (by virtue of greater specificity) if the investigator brochure only listed cerebral vascular accidents. “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.

Review of Safety Information The sponsor-investigator should promptly review all information relevant to the safety of the drug obtained or otherwise received by the sponsor-investigator from any source, foreign or domestic, including information derived from any clinical or epidemiological investigations, animal investigations, commercial marketing experience, reports in the scientific literature, and unpublished scientific papers, as well as reports from foreign regulatory authorities that have not already been previously reported to the FDA by the sponsor- investigator.

IND Safety Reports

Written reports are used by the sponsor-investigator to notify the FDA as well as all participating investigators of: 1. Any adverse experience associated with the use of the drug that is both serious and unexpected; 2. Any finding from tests in laboratory animals that suggests a significant risk for human participants including reports of mutagenicity, teratogenicity, or carcinogenicity. Each notification should be made as soon as possible and in no event later than 15 calendar days after the sponsor-investigator is initially notified of the event.

Each written notification may be submitted on FDA form 3500A or in a narrative format (foreign events may be submitted either on an FDA form 3500A or, if preferred, on a CIOMS I form; reports from animal or epidemiological trials should be submitted in a narrative format) and should bear prominent identification of its contents (i.e., IND Safety Report).

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Each written notification to the FDA should be transmitted to the FDA new drug review division in the Center for Drug Evaluation and Research or the product review division in the Center for Biologics Evaluation and Research that has responsibility for review of the IND

In each written IND safety report, the sponsor-investigator should identify all safety reports previously filed with the IND concerning a similar adverse experience, and should analyze the significance of the adverse experience in light of the previous, similar reports.

Telephone and facsimile transmission safety reports are utilized by the sponsor-investigator to notify FDA of any unexpected and fatal/life-threatening adverse drug experiences that are associated with use of the experimental drug. The sponsor-investigator should notify the FDA by telephone or fax of any unexpected and fatal or life- threatening experience associated with the use of the drug as soon as possible but in no event later than 7 calendar days after the sponsor-investigator is initially notified of the event. Each telephone call or fax to the FDA should be transmitted to the FDA new drug review division in the Center for Drug Evaluation and Research or the product review division in the Center for Biologics Evaluation and Research that has responsibility for review of the IND.

Reporting format or frequency. The FDA may request that the sponsor-investigator submit IND safety reports in a format or at a frequency different than that required under this paragraph. The sponsor- investigator may also propose and adopt a different reporting format or frequency if the change is agreed to in advance by the director of the new drug review division in the Center for Drug Evaluation and Research or the director of the products review division in the Center for Biologics Evaluation and Research that is responsible for review of the IND.

Marketed Drug: The sponsor-investigator of a clinical trial of a marketed drug is not required to make a safety report for any adverse experience associated with use of the drug that is not from the clinical trial itself.

Follow-up Action to an IND Safety Report

The sponsor-investigator is obligated to promptly investigate any follow-up information received about the adverse drug experience. All follow-up information to an IND Safety Report should be submitted to the FDA as soon as the relevant information is available. In studies using marketed drug(s), the sponsor-investigator should follow-up on reports only for those drugs in connection with the adverse experience that derive from the use of the drug as a result of the study. If the sponsor-investigator’s review shows that an adverse drug experience not initially determined to be reportable under the previous part of this section is so reportable, the sponsor-investigator should report such experience in a written safety report as soon as possible, but in no event later than 15 calendar days after the determination is made. The sponsor-investigator should report the results of other safety information, as appropriate, in either an information amendment or annual report.

34.9 IND Annual Report 21 CFR 312.33

The purpose and focus of the annual reports is to keep FDA informed of the progress of the clinical study during the year and the investigational plan for the upcoming year. A system should be put in place at the

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beginning of the IND process to routinely collect information that will need to be submitted in the annual report.

An annual report is due within 60 days (+/-) of the anniversary date that the IND went into effect. DF/HCC strongly encourages the sponsor-investigator to submit the annual progress report to FDA at the time he/she files a continuing review form with the DFCI IRB. An annual report should comprise a brief progress report of the investigation.

The content of the IND Annual Report is as follows: 1. Individual study information summarizing all studies under the IND; 2. Summary information of the year’s clinical and non-clinical results; 3. General investigational plan for the coming year as per 21 CFR 312.23 (3). The content must be distinct from and replace the plan submitted for the previous year; 4. A description of any revisions to the investigator’s brochure. A copy of the newly revised brochure must be included with the annual report; 5. A description of any significant protocol modification made during the previous year and not previously reported to FDA as an IND protocol amendment; 6. A brief summary of any significant events in foreign marketing of the drug during the past year including marketing approval as well as withdrawal/suspension of marketing privileges in any foreign country; 7. Any outstanding IND related business to which a reply, comment or scheduled meeting with FDA is expected or requested. Note: Submission of the IND Annual Report does not preclude the sponsor-investigator’s responsibility to submit Continuing Review/Progress Reports to the reviewing IRB.

34.10 Final Study Reports

A final report should be written and submitted for all IND applications. The final report should be submitted as soon as the clinical studies have concluded or within six months of study completion.

34.11 Withdrawal of an IND Application 21 CFR 312.38

A sponsor-investigator may choose to withdraw an effective IND at any time without prejudice, however the withdrawn IND cannot be reactivated nor can it continue to be referenced in other IND applications.

When an IND is withdrawn the sponsor-investigator must complete these steps: 1. Cease conducting all clinical investigations under the IND; 2. Notify all participating investigators that the IND has been withdrawn; 3. Request the return of all unused stocks of drug and dispose of them in a manner that does not put anyone at risk per 21 CFR 312.59; 4. Notify the FDA in writing that the IND is being withdrawn with the reason the IND is being withdrawn.

Note: The sponsor-investigator must promptly notify the FDA, all participating investigators, and all reviewing IRBs when an IND is withdrawn because of safety concerns. A reason for the withdrawal should be given.

34.12 General Responsibilities of the Sponsor-Investigator

According to 21 CFR 312.50 the sponsor-investigator is responsible for selecting qualified investigators, providing them with the information necessary to conduct an investigation properly, ensuring proper

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monitoring of the investigation(s), ensuring that the investigation(s) is conducted in accordance with the general investigational plan and protocols contained in the IND, maintaining an effective IND with respect to the investigations, and ensuring that the FDA and all participating investigators are promptly informed of significant new adverse effects or risks with respect to the drug.

34.13 Selecting Participating Investigators and Monitors

The investigator has the following obligations as outlined in 21 CFR 312.53.

Selecting Investigators The sponsor-investigator should select only investigators qualified by training and experience as appropriate experts to investigate the drug.

Control of Drug The sponsor-investigator must ship investigational new drugs only to investigators participating in the investigation.

Obtaining information from the Participating Investigator(s) Before permitting a participating investigator to begin participation in an investigation, the sponsor- investigator should:

1. Obtain a signed investigator statement (FDA form 1572);

2. Obtain a curriculum vitae (CV) or other statement of qualifications of the investigator showing the education, training, and experience that qualifies the investigator as an expert in the clinical investigation of the drug for the use under investigation;

3. Provide the participating investigator a copy of the protocol: For Phase I investigations, a general outline of the planned investigation including the estimated duration of the trial and the maximum number of subjects that will be involved. For Phase II or Phase III investigations, an outline of the trial protocol including an approximation of the number of subjects to be treated with the drug and the number to be employed as controls, if any; the clinical uses to be investigated; characteristics of subjects by age, sex, and condition; the kind of clinical observations and laboratory tests to be conducted; the estimated duration of the trial; and copies or a description of case report forms to be used.

Selecting Monitors

The sponsor-investigator should select a monitor qualified by training and experience to monitor the progress of the investigation.

34.14 Informing Participating Investigators of New Observations

Before the investigation begins, the sponsor-investigator should give each participating investigator an investigator brochure containing the information described in 21 CFR 312.23 (a)(5) if and when such a document exists.

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The sponsor-investigator should, as the overall investigation proceeds, keep each participating investigator informed of new observations discovered by or reported to the sponsor-investigator on the drug, particularly with respect to adverse effects and safe use. Such information may be distributed to participating investigators by means of periodically revised investigator brochures, reprints or published trials, reports or letters, or other appropriate means. Important safety information should also be relayed to participating investigators in accordance with 21 CFR 312.32.

34.15 Review of Ongoing Investigations 21 CFR 312.56

The sponsor-investigator should monitor the progress of all clinical investigations being conducted under the IND.

A sponsor-investigator who discovers that a participating investigator is not complying with the signed agreement (FDA form 1572), the general investigational plan, or the requirements of the trial, should promptly either secure compliance or discontinue shipments of the IND to the participating investigator and end the participating investigator's involvement in the investigation. If the participating investigator’s involvement in the investigation is ended, the sponsor-investigator should require that the participating investigator dispose of or return the investigational drug in accordance with the requirements of the protocol. These actions should be reported to the FDA.

The sponsor-investigator should review and evaluate the evidence relating to the safety and effectiveness of the drug as it is obtained from the participating investigator. The investigator should make such reports to the FDA regarding information relevant to the safety of the drug as are required by the regulations. The investigator should make annual reports on the progress of the investigation.

A sponsor- investigator who determines that the investigational drug presents an unreasonable and significant risk to participants should discontinue those investigations that present the risk, notify the FDA, all IRBs, and all participating investigators who have at any time participated in the investigation of the discontinuance, assure the disposition of all stocks of the drug outstanding as required, and furnish the FDA with a full report of the actions. The sponsor-investigator should discontinue the investigation as soon as possible, and in no event later than 5 working days after making the determination that the investigation should be discontinued. Upon request, the FDA will confer with the investigator on the need to discontinue an investigation.

34.16 Record Keeping and Record Retention

21 CFR 312.57 A sponsor-investigator should maintain and/or retain the following: 1. Adequate records showing the receipt, shipment, or other disposition of the investigational drug. These records are required to include, as appropriate, the name of the participating investigator to whom the drug is shipped, and the date, quantity, and batch or code mark of each such shipment. 2. Records and reports required by this part for 2 years after a marketing application is approved for the drug; or, if an application is not approved for the drug, until 2 years after shipment and delivery of the drug for investigational use is discontinued and the FDA has been so notified. 3. Reserve samples of any test article and reference standard identified in, and used in any of the bioequivalence or bioavailability trials, and release the reserve samples to the FDA upon request, in accordance with, and for the period specified in 21 CFR 320.38.

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34.17 Inspection of Records and Reports 21 CFR 312.58

FDA Inspection

The sponsor-investigator should upon request from any properly authorized officer or employee of the FDA, at reasonable times, permit such officer or employee to have access to and copy and verify any records and reports relating to a clinical investigation conducted under this IND. Upon written request by the FDA, the sponsor-investigator should submit the records or reports (or copies of them) to the FDA. The sponsor-investigator should discontinue shipments of the drug to any participating investigator who has failed to maintain or make available records or reports of the investigation as required.

34.18 Disposition of Unused Investigational Drug 21 CFR 312.59

The sponsor-investigator should assure the return or destruction of all unused supplies of the participating investigators.

34.19 General Responsibilities of Participating Investigator

A participating investigator is responsible for ensuring that the investigation at his or her institution is conducted according to the signed investigator statement (FDA form 1572), the investigational plan and applicable regulations; for protecting the rights, safety, and welfare of participants under the participating investigator’s care; and for the control of drugs under investigation at his or her institution. A participating investigator should, in accordance with the provisions of 21 CFR Part 50, obtain the informed consent of each human participant to whom the drug is administered. Participating investigators must also comply with all regulations set forth in 21 CFR Part 56, and 45 CFR Part 46.

34.20 Control of the Investigational Drug 21 CFR 312.61 Participating investigators should administer the drug only to participants under their personal supervision or under the supervision of a sub-investigator responsible to them. Participating investigators should not supply the investigational drug to any person not authorized to receive it.

34.21 Participating Investigator Record Keeping and Record Retention

Disposition of Drug A participating investigator is required to maintain adequate records of the disposition of the drug, including dates, quantity, and use by participants. If the investigation is terminated, suspended, discontinued, or completed, the participating investigator should return the unused supplies of the drug to the sponsor- investigator, or otherwise provide for disposition of the unused supplies of the drug.

Case Histories A participating investigator is required to prepare and maintain adequate and accurate case histories that record all observations and other data pertinent to the investigation on each individual administered the investigational drug or employed as a control in the investigation. Case histories include the case report forms and supporting data including, for example, signed and dated consent forms and medical records including, for example, progress notes of the physician, the individual’s hospital chart(s), and the nurses’

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notes. The case history for each individual should document that informed consent was obtained prior to participation in the trial.

Record Retention A participating investigator should retain records required to be maintained for a period of 2 years following the date a marketing application is approved for the drug for the indication for which it is being investigated; or, if no application is to be filed or if the application is not approved for such indication, until 2 years after the investigation is discontinued and the FDA is notified.

34.22 Participating Investigator Reports

Progress Reports

Participating investigators should furnish all data and/or requested by the sponsor-investigator. The sponsor- investigator is required to collect and evaluate the results obtained and to submit annual reports to the FDA on the progress of the clinical investigations.

Safety Reports

A participating investigator should promptly report to the sponsor-investigator any adverse effect that may reasonably be regarded as caused by, or probably caused by, the drug. If the adverse effect is alarming, the participating investigator should report the adverse effect immediately.

Final Report

A participating investigator should provide the sponsor-investigator with an adequate report shortly after completion of the participating investigator's involvement in the investigation.

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Section 35 - Conducting Investigator-Sponsored Multi-center Trials at DF/HCC

An Overall Principal Investigator (PI) of a DF/HCC Investigator-Sponsored protocol may extend a trial to investigators from institutions that are external to the DF/HCC umbrella (and external to the DF/PCC affiliate network). In these cases, the PI is ultimately responsible for the conduct of the trial at all participating sites, both within DF/HCC and at the external institutions. The home institution of the Overall PI is typically designated as the Coordinating Center (Lead Site) for the study. The Coordinating Center is designated the responsibility for managing all trial related documents and data.

The Multi-Center Coordinating Committee (MCC) approves all sites external to DF/HCC and the DF/PCC Network Affiliates prior to submission to the DFCI IRB.

The DFCI IRB will not serve as the IRB of record for any International Research sites, including DoD funded research.

This section provides an overview of the processes and oversight that an Overall PI and Coordinating Center should have in place to ensure proper study management. For more information, please refer to the DF/HCC clinical research policy governing multi-center trials, SOP MULTI-100.

35.1 Purpose and Function of a Coordinating Center

The Coordinating Center provides administrative, data management, and organizational support in the conduct of the multi-center trial. It functions as the central location for trial documents and subject registration, and monitors the conduct and progress of the clinical trial at all participating sites.

35.2 Overall PI Responsibilities

The DF/HCC Overall PI has ultimate responsibility for the conduct of the study, and for monitoring its safety and progress, at all participating sites. The Overall PI is also responsible for the coordination, development, submission, and approval of the protocol, and its subsequent amendments. It is the responsibility of the Overall PI to ensure that all participating sites are using the correct version of the protocol. The model research consent document must include a statement that data will be shared with DF/HCC or its agents (which may include an outside CRO, medical monitor, ODQ, Data and Safety Monitoring Board/Data and Safety Monitoring Committee and the Lead Institution’s research team).

Additional responsibilities of the Overall PI include:  Study staff training  Fulfilling all regulatory reporting requirements  Timely review of all adverse event (AE) reports from all sites  Review of all study data submitted for analysis  Regular communication with all participating sites  Delegation of specific study roles for ongoing trial management

Note: An Overall PI who holds an IND is bound to the investigator and sponsor requirements written in 21 CFR Part 312.

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35.3 Coordinating Center Responsibilities

The Coordinating Center manages the regulatory documents and central participant registration process with ODQ for each participating site, establishes procedures for submitting adverse events and unexpected problems involving research to the Overall PI and appropriate oversight entities, coordinates staff training, and facilitates monitoring and auditing visits.

35.4 Participating Site PI Responsibilities Site PIs are responsible for the conduct of the trial at their individual site. It is the responsibility of the Site PI to ensure that his or her study team uses the current version of protocol and informed consent documents and that the study team is conducting the clinical trial in compliance with all local and federal regulations.. Additional responsibilities of the Participating Site PI include:

 Designating a study coordinator and/or research nurse as the study contact  Timely submission of study data  Prompt reporting of adverse events (AEs) and unexpected problems involving research to their IRB and to the DF/HCC Overall PI

35.5 Regulatory Files Each site must compile a regulatory binder specific to its function. The documents should be maintained or updated, as appropriate, throughout the course of the trial. Refer to DF/HCC SOP RCO-203 for the contents of the Lead Site and Non-Lead Site regulatory binders within the DF/HCC and DF/PCC affiliate network. Please refer to the ODQ website for regulatory binder instructions for sites external to DF/HCC.

35.6 Staff Training

The Overall PI must ensure that all participating Site PIs and study staff are trained on the conduct of the protocol, study procedures, applicable DF/HCC requirements (i.e. consent procedures, AE reporting, deviation/violation reporting, and data collection). This may be accomplished through on- site visits or via teleconference. The general areas to be discussed should include, but are not limited to:  Study design and procedures  Informed Consent and registration procedures  Adverse event reporting procedures and requirements  Data Collection and Submission  Ongoing meeting procedures  Monitoring and auditing arrangements  Pharmacy and drug administration procedures  Participating site responsibilities and documentation

35.7 Central Participant Registration

The DF/HCC ODQ) serves as the central location for registering all participants enrolled in a DF/HCC trial. The ODQ maintains a participant registration list and a copy of each eligibility checklist and signed consent form.

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35.8 Adverse Event Reporting

The Overall PI is responsible for the timely review of all AE reports to assure the safety of participants. The Coordinating Center is the central location for the collection and maintenance of adverse event documentation and promptly submits AE reports to the Overall PI.

The Coordinating Center maintains documentation of all adverse events in the regulatory files for each site. Each participating site maintains its own documentation as required.

All adverse events must be reported to the Coordinating Center in accordance with the DF/HCC IRB Reporting Policy for Adverse Events. Participating sites will also report adverse events to their local IRB according to their institutional policy for reporting adverse events.

Note: An investigator that is conducting the trial as the IND holder is responsible for reporting to FDA. Participating sites will report to the Overall PI and not directly to the FDA on a sponsor-investigator trial 21 CFR Part 312 and DF/HCC SOP RCO-203.

35.9 Data Collection

The participating sites should enter data and submit case report forms (CRFs) to the Coordinating Center in a timely manner. For paper case report forms, the Coordinating Center will forward the completed forms to the ODQ. Sites may also be required to send source documentation to DF/HCC.

35.10 Quality Assurance

The Overall PI is responsible for the integrity and accuracy of data collected at each participating site. The monitoring and auditing plans* should be based on the complexity and risk level of the trial and should be consistent with the standards outlined in the DF/HCC Clinical Trials Audit Manual. Typical monitoring and auditing visits may include review of original consent forms, case report forms and source documentation, treatment administration records, protocol compliance, and drug accountability. Sites should be aware that they might be audited by the DF/HCC in addition to any oversight delegated to an external Contract Research Organization (CRO).

*Refer to the DF/HCC Multi-center DSMP on the DFHCC website.

35.11 Site Communication

The Overall PI and Coordinating Center should have regular and documented communications with the participating sites to update and inform them about the progress of the trial.

35.12 Drug Ordering

Each participating site is responsible for the ordering, storing and dispensing of investigational agent(s) from the organization or company that is supporting the trial.

35.13 Inter-institutional Agreement/Contract

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A formal agreement/contract is generally required. The agreement must be reviewed and approved by the DF/HCC Research Administration Office.

35.14 Multi-center Coordinating Committee (MCC) The MCC was created in November 2007 to provide assistance to the PI and study team in the development of a PI-initiated multi-center trial and to assure compliance with DF/HCC SOP MULTI-100. The MCC reviews all multi-center trials prior to the research being extended to an external site. New multi-center trials are reviewed by the MCC prior to being submitted to the IRB. Please refer to the DFHCC for the procedures and templates.

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Section 36 - Gene Transfer Research (recombinant DNA)

If a given study involves recombinant DNA, additional review and reporting requirements apply.

“Human gene transfer is the deliberate transfer into human research participants of either recombinant nucleic acid molecules, or DNA or RNA derived from recombinant nucleic acid molecules, or synthetic nucleic acid molecule. Human gene transfer research often raises scientific, medical, ethical, and social considerations worthy of special attention and public discussion. Some of these issues arise from the fact that the techniques being used are relatively new and their risks and benefits are not well characterized”. (http://osp.od.nih.gov/office-biotechnology-activities/biomedical-technology-assessment/hgt).

NIH Office of Biotechnology (OBA):

In addition to the FDA and IRBs, the National Institutes of Health Office for Biotechnology Activities (OBA) and Institutional Biosafety Committees are charged with review and oversight of human gene transfer trials.

All Institutions that accept NIH grant funding must adhere to the: NIH Guidelines for Research involving recombinant or synthetic nucleic acid molecules, for all trials, including industry-sponsored trials.

The NIH Guidelines are found at: http://osp.od.nih.gov/sites/default/files/NIH_Guidelines.html#_Toc351276401

 Please refer specifically to: Appendix M Points to Consider in the Design and Submission of Protocols for the Transfer of Recombinant DNA Molecules Into One or More Human Research Participants outlines the submission requirements in M-1-A.

After receiving the proposed research, an NIH Committee, the Recombinant DNA Advisory Committee (RAC), will decide whether the trial presents novel characteristics that warrant public RAC review and discussion in addition to local Institutional Biosafety Committee review. If the trial is not selected for public review, only local Institutional Biosafety Committee review is required, in addition to IRB review.

Trial activation does not occur until all requirements of the FDA, IRB, NIH, and Institutional Biosafety Committee, and the conditions set by departmental reviews, are met. Additional reporting requirements for human gene transfer studies are outlined in Appendix M of the NIH guidelines.

Safety Reporting:

The Genetic Modification Clinical Research Information System (GeMCRIS) is a web-based information system for human gene transfer trials that was developed in collaboration with the Food and Drug Administration (FDA) and is designed to facilitate safety reporting. Investigator and sponsors of a human gene transfer trials can utilize this system to report adverse events (AEs) and annual reports. GeMCRIS is also a searchable database listing of all human gene transfer trials registered with NIH.

Institutional Biosafety Committees:

Institutional Biosafety Committee approval is required at each trial site; contact information is listed below. A process similar to the cede review process of the DF/HCC IRBs is under development by Harvard Catalyst, ODQ will be informed when this review process is available.

Boston Children’s Hospital: Contact: Despina Felis ([email protected])

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Dana-Farber Cancer Institute: Contact: Karen Byers ([email protected])

Forsyth Institute: Contact: Kathy Eklund ([email protected])

Harvard COMS: http://hms.harvard.edu/departments/committee-microbiological-safety

Contact: Rebecca Caruso ([email protected]) Harvard COMS conducts IBC review for the following institutions:  Beth Israel Deaconess Medical Center,  Joslin Diabetes Research Center,  Harvard Medical School  Harvard School of Dental Medicine  Harvard School of Public Health  Harvard University Faculty of Arts and Sciences  Massachusetts Eye and Ear Infirmary  Schepens Eye Research Institute

Partners Healthcare IBC: http://resadmin.partners.org/RM_Home/Research_Support_Depts/Research_Oversight/PIBC/About/AboutPI BC.aspx

Contact: Leslie Hofherr ([email protected]) Partners Healthcare IBC conducts IBC review for the following institutions:  Brigham and Women’s Hospital  Massachusetts General Hospital  McLean Hospital  Spaulding Rehabilitation Hospital Network

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Section 37 – Evaluation of Outreach Activities and Catchment Area

As a cancer center that is required to abide by the NCI Cancer Center Support Guidelines (CCSG), the DF/HCC is required to have an External Advisory Board (EAB) review on an annual basis the DF/HCC cancer program in between the five year grant renewals. The EAB membership consists of individuals from cancer centers throughout the country. Part of the review of the EAB is to look at the catchment area of the cancer center and the outreach activities. The EAB provides the DF/HCC with a critic which is addressed each year by the DF/HCC in the annual progress reviews provided to the NCI.

One program within the DF/HCC that is reviewed by the EAB annually is the DF/HCC Initiative to Eliminate Cancer Disparities (IECD). DF/HCC created the IECD to provide a centralized and coordinated structure for addressing the complexities of cancer disparities – it was among the nation’s first integrated, inter-institutional, multi-pronged approaches.

As a centralized initiative, the IECD is transforming how member institutions work together, bringing intellectual and organizational resources to bear on cancer disparities issues. The IECD coordinates and complements the activities of each individual institution by providing an infrastructure for advancing community outreach, promoting disparities research, and raising awareness of and sensitivity to the impact of culture on the disease of cancer, medical decision- making, and care. Its activities permeate all seven DF/HCC member institutions, providing an unparalleled opportunity to eliminate cancer disparities.

To advance DF/HCC’s commitment to eliminating disparities across all levels of cancer research, clinical care, and institutional administration the IECD emphasizes six key areas:

 Enhancing research on cancer disparities, particularly within disease-based programs  Supporting faculty diversity  Amplifying culturally competent care throughout DF/HCC institutions  Engaging diverse communities on the subjects of cancer prevention and care  Facilitating the access of underserved populations to clinical trials  Forging relationships with schools that serve underrepresented populations, expanding biomedical training in minority communities

More information about the IECD is available on the DF/HCC website at: www.dfhcc.harvard.edu/cancer-disparities

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REFERENCES

R.1 Code of Federal Regulations

Electronic Code of Federal Regulations (e-CFR): http://www.ecfr.gov/cgi-bin/ECFR?page=browse

The Electronic Code of Federal Regulations (e-CFR) is a currently updated version of the Code of Federal Regulations (CFR). The e-CFR is an editorial compilation of CFR material and Federal Register amendments produced by the National Archives and Records Administration's Office of the Federal Register (OFR) and the Government Printing Office.

R.2 Good Clinical Practice Guidelines

Guidance for Industry – Good Clinical Practice www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM129515.pdf

R.3 Medical Terminology, Dictionaries and Other Resources

NCCN Informed Consent Language (ICL) Database: http://www.nccn.org/clinical_trials/informed_consent.aspx

NCI Common Terminology Criteria for Adverse Events (CTCAE): http://evs_nci.nih.gov/ftp1/CTCAE/about.html

ECOG Performance Status: www.ecog.org/general/perf_stat.html

R.4 Ethics References

Nuremberg Code: http://www.hhs.gov/ohrp/archive/nurcode.html

Declaration of Helsinki: http://www.wma.net/en/30publications/10policies/b3

Belmont Report http://www.hhs.gov/ohrp/humansubjects/guidance/belmont.html

R.5 External Web Sites

Office for Human Research Protections (OHRP): www.hhs.gov/ohrp

Food & Drug Administration (FDA): www.fda.gov Includes Access to:  Instructions for Sponsor-Investigators Submitting IND Applications

National Institutes of Health (NIH): www.nih.gov

Office for Civil Right (OCR) – HIPAA: www.hhs.gov/ocr/privacy/index.html

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National Cancer Institute (NCI): www.cancer.gov

National Cancer Institute Central IRB (NCI CIRB): www.ncicirb.org

Cancer Therapy Evaluation Program (CTEP): ctep.cancer.gov

Cancer Trials Support Unit (CTSU): www.ctsu.org

Quality Assurance Review Center (QARC): www.qarc.org

Office of Biotechnology Activities (OBA): http://osp.od.nih.gov/office-biotechnology-activities

National Clinical Trials Network (NCTN):  Alliance for Clinical Trials in Oncology (Alliance): www.allianceforclinicaltrialsinoncology.org  NRG Oncology: www.nrgoncology.org  Children’s Oncology Group (COG): www.childrensoncologygroup.org

R.6 DF/HCC Web Sites

DF/HCC: http://www.dfhcc.harvard.edu/

DF/HCC Clinical Research Support: http://www.dfhcc.harvard.edu/clinical-research-support/

Includes Access to:  Office for Human Research Studies (OHRS)  Office of Data Quality (ODQ)  Clinical Trials Education  Clinical Investigations Leadership Committee (CLC)  Clinical Trials Research Informatics Office (CTRIO)  Protocol Review and Monitoring System (PRMS)  OnCore (CTMS)

DF/HCC Cancer Disparities: http://www.dfhcc.harvard.edu/cancer-disparities/

R.7 DF/HCC Participating Institutions

Beth Israel Deaconess Medical Center (BIDMC) 330 Brookline Avenue Boston, Massachusetts 02215 617-667-7000

Boston Children's Hospital (BCH) 300 Longwood Avenue Boston, Massachusetts 02115 617-355-6000

Brigham and Women's Hospital (BWH) 75 Francis Street Boston, Massachusetts 02115 617-732-5500

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Dana-Farber Cancer Institute (DFCI) 450 Brookline Avenue Boston, Massachusetts 02215 617-632-3000

Harvard Medical School (HMS) 25 Shattuck Street Boston, Massachusetts 02115 617-432-1000

Harvard School of Public Health (HSPH) 667 Huntington Avenue Boston, Massachusetts 02115 617-432-1000

Massachusetts General Hospital (MGH) 55 Fruit Street Boston, Massachusetts 02114 617-726-2000

R.8. Regulatory Documents for Sponsors: http://www.dfhcc.harvard.edu/research/clinical-research-support/ 1. DF/HCC Site Management Plan DF/HCC Site Management Plan 2. DF/HCC Practice Differences in Comparison to ICH GCP Guidelines DF/HCC Practice Differences in Comparison to ICH GCP Guidelines 3. OHRS letter for sponsors detailing DFCI IRB procedures Letter from OHRS for Sponsors Outlining DFCI IRB Procedures 4. 21 CFR Part 11 letters BIDMC 21 CFR Part 11 letter 5. Partners 21 CFR Part 11 letter 6. DEA letters BIDMC DEA 7. DFCI DEA 8. MGH DEA

R.9. DF/HCC SOPs for Human Subject Research: http://www.dfhcc.harvard.edu/research/clinical-research-support/document-library-forms-sops- etc/dfhcc-sop-library/ Administration (ADM) SOPs 1. ADM-100 (formerly GA-101): Writing and Revising DF/HCC Standard Operating Procedures a. Helpful Resource: DF/HCC SOP Signature Page b. Helpful Resource: DF/HCC SOP Template c. Helpful Resource: Guidance on Format Requirements for Standard Operating Procedures (SOPs) 2. ADM-101 (formerly GA-102): Use of the DF/HCC Research Listserv 3. ADM-102 (formerly GA-103): Maintenance of the Oncology Protocol System (OncPro) Priority List

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4. ADM-103 (formerly QA-714): Maintenance of Association for the Accreditation of Human Research Protection Programs (AAHRPP) Accreditation

Audit (AUD) SOPs 1. AUD-100 (formerly QA-720): Internal Auditing of Clinical Research 2. AUD-101 (formerly QA-719): Audit Preparation and Response a. Helpful Resource: Guidance on Hosting External Audits and Regulatory Agency Inspections b. Helpful Resource: Guidance on Responding to Audit Findings 3. AUD-102 (formerly QA-706): External Audits of DF/HCC Clinical Research a. Helpful Resource: External Audit Contact List b. Helpful Resource: Guidance on Hosting External Audits and Regulatory Agency Inspections c. Helpful Resource: Sample IND/IDE Responsibility Checklist

Committee (COM) SOPs 1. COM-100 (formerly QA-704): Responsibilities of the Clinical Research Operations Committee (CLINOPS) 2. COM-101 (formerly QA-702): Responsibilities of the Audit Committee 3. COM-102 (formerly QA-710): Accrual and Scientific Progress by the SRC 4. COM-103 (formerly QA-701): Responsibilities of the Clinical Investigations Leadership Committee (CLC)

Consent (CON) SOPs 1. CON-100 (formerly SM-506):Informed Consent Process a. Helpful Resource: Guidance on Documenting Informed Consent b. Helpful Resource: Informed Consent Verification Checklist 2. CON-101 (formerly SM-507): Obtaining Informed Consent of Non-English Speakers 3. CON-102 (formerly SM-505): Use of Healthy Volunteers 4. CON-103 (formerly SS-306): Enrolling Subjects onto Secondary Studies Evaluating Research

Data Management (DATA) SOPs 1. DATA-100 (formerly QA-717): Data Management of PI-Initiated Therapeutic Protocols a. Helpful Resource: Protocol Data Request Form 2. DATA-101 (formerly QA-715): Case Report Form (CRF) Design for PI-Initiated Protocols

a. Helpful Resource: Biostatistics CRF Review Waiver 3. DATA-102 (formerly PM-413): Case Report Form (CRF) Compliance for External Sponsors 4. DATA-103 (formerly QA-716): Case Report Form (CRF) Submission Compliance for PI-Initiated Protocols 5. DATA-104 (formerly QA-724): Data and Safety Monitoring Committee (DSMC) Data Submission Compliance

Documentation (DOC) SOPs 1. DOC-100 (new): Subject Research Charts 2. DOC-101 (formerly PM-417): Source Documentation Requirements a. Helpful Resource: Guidance on Source Documents b. Helpful Resource: Guidance on Good Study Documentation Practices 3. DOC-102 (formerly PM-415): Note to File

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a. Helpful Resource: Note to File Template

Education & Training (EDU) SOPs 4. EDU-100 (formerly ET-203): Protocol Specific Training Requirements 5. EDU-101 (formerly ET-201): Standard Operating Procedure (SOP) Training Requirements a. Helpful Resource: Role Matrix for Responsible Personnel 6. EDU-102 (formerly ET-204): Human Subject Protection Training Requirements 7. EDU-103 (formerly ET-205): Good Clinical Practice Training Requirements for New Researchers 8. EDU-104 (formerly QA-722): Audit Training Requirements for New Clinical Researchers 9. EDU-105 (formerly QA-723): Training Requirements for New Overall Principal Investigators

Investigational Product (INV) SOPs 1. INV-100 (formerly PM-403): Research Pharmacy Standard Procedures 2. INV-101 (new): Transfer of Investigational Drug 3. INV-102 (formerly PM-404): Return of Unused Investigational Drug from Subject to the Pharmacy 4. INV-103 (formerly PM-406): Protocol Mandated Drug Taken at Home a. Helpful Resource: Guidance on Creating a Drug Diary b. Helpful Resource: Drug Diary Template - Multiple Drugs c. Helpful Resource: Drug Diary Template - One Drug

Monitoring (MON) SOPs 1. MON-100 (formerly QA-708): Monitoring Phase I Dose Escalation for PI-Initiated Protocols a. Helpful Resource: OHRS Alert Page Template b. Helpful Resource: OHRS Amendment Submission Form c. Helpful Resource: In-House Phase I Clinical Trials Dose Escalation Form 2. MON-101 (formerly QA-721): Routine Monitoring Visits by External Sponsors a. Helpful Resource: Guidance on Investigator Interactions with Monitors

Multi-Center Trial (MULTI) SOPs 1. MULTI-100 (formerly PM-402): Conducting PI-Initiated Multi-Center Trials a. Helpful Resource: Multi-center Coordinating Center Checklist b. Helpful Resource: Data and Safety Monitoring Plan Template c. Helpful Resource: Multi-center Trials Forms, Guidance and Study Start-Up Tools d. Helpful Resource: Participating Institution Regulatory Binder Instructions (for external sites) e. Helpful Resource: Procedures for Submission of PI-Initiated Multi-center Protocols f. Helpful Resource: Sponsor Regulatory File Checklist 2. MULTI-101: Training Requirements for DFHCC Sponsors and new personnel on Multicenter studies

Research Close Out (RCL) SOPs 1. RCL-100 (formerly PM-416): Preparation for Site Close Out a. Helpful Resource: Sample Research Close Out Checklist 2. RCL-101 (formerly PM-401): Record Retention for Completed Research

Research Conduct (RCO) SOPs 1. RCO-100 (formerly PM-408): Responsibilities of the Sponsor Conducting Research Involving a Drug a. Helpful Resource: Form FDA 3500A (Mandatory MedWatch Form)

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b. Helpful Resource: List of Institutional IND Contacts 2. RCO-101 (formerly PM-418): Responsibilities of the Sponsor Conducting Research Involving a Device 3. RCO-102: Responsibilities of Investigators a. Helpful Resource: Guidance on Developing a Supervisory Plan for Clinical and Non-Clinical Research b. Helpful Resource: Sample Joint Meeting Agenda c. Helpful Resource: Sample Joint Meeting Communication Record d. Helpful Resource: Supervisory Plan for Clinical and Non-Clinical Research 4. RCO-103 (formerly PM-412): Confidentiality of Research Information 5. RCO-200 (formerly ET-202): Documenting Delegation of Authority a. Helpful Resource: Guidance on Delegation of Tasks for Research Involving a Drug or Device b. Helpful Resource: Sample Group Delegation of Authority and Signature Log c. Helpful Resource: Sample Individual Delegation of Authority and Signature Log 6. RCO-201 (formerly PM-411): Completion of Form FDA 1572 7. RCO-202 (formerly PM-410): Research Personnel CVs and Licenses 8. RCO-203 (formerly PM-409): Managing Essential Regulatory Documents a. Helpful Resource: Guidance on Maintaining Regulatory Documents b. Helpful Resource: Master Regulatory File Checklist for Lead Site c. Helpful Resource: Regulatory File Checklist for Network Affiliates d. Helpful Resource: Regulatory File Checklist for Non-Lead and Satellite Sites e. Helpful Resource: Sponsor Regulatory File Checklist 9. RCO-204 (formerly AE-601): Reporting Adverse Events a. Helpful Resource: DFCI IRB Serious Adverse Event Reporting Form b. Helpful Resource: NCI Common Toxicity Criteria for Adverse Events (CTCAE) 10. RCO-205 (formerly PM-407): Reporting of Protocol Deviations, Exceptions and Violations a. Helpful Resource: DFCI IRB Major Deviation/Violation/Exception/Other Event Reporting Form b. Helpful Resource: DFCI IRB Minor Deviation/Violation Log c. Helpful Resource: Guidance on Reviewing Protocol Departures and Developing Corrective Actions 11. RCO-206 (formerly PM-405): Overall Principal Investigator or Site Responsible Investigator Leave of Absence 12. RCO-207 (formerly SM-502): Performance of Protocol Specified Procedures at Non-DF/HCC Sites

Registration (REGIST) SOPs 1. REGIST-100 (formerly QA-711): Internal Eligibility Checklist 2. REGIST-101A (formerly QA-712 & QC-804): Centralized Subject Protocol Registration 3. REGIST-101B : De-Centralized Subject Protocol Registration 4. REGIST-102 (formerly SM-503): Subject Removal from a Protocol a. Helpful Resource: ODQ Treatment Ended/Off Study Form 5. REGIST-103 (formerly SM-504): Transfer of Subjects between Institutions a. Helpful Resource: Subject Transfer Form 6. REGIST-104: Using the Eligibility Checklist 7. REGIST-200 (formerly SS-301): Registration of Clinical Trials on ClinicalTrials.gov a. Helpful Resource: How/When to Register a Protocol on ClinicalTrials.gov (overview) b. Helpful Resource: Step by Step Guidance for Registering a Protocol on ClinicalTrials.gov c. Helpful Resource: How to Determine Primary Completion and Study Completion Date

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d. Helpful Resource: Common Mistakes Found Within ClinicalTrials.gov Records e. Helpful Resource: DF/HCC Contacts for ClinicalTrials.gov Accounts and Initial Registration 8. REGIST-201 (formerly SS-307): Posting Results and Adverse Events on ClinicalTrials.gov a. Helpful Resource: How/When to Submit Results to ClinicalTrials.gov b. Helpful Resource: Step by Step Guidance for Registering a Protocol on ClinicalTrials.gov c. Helpful Resource: Common Mistakes Found Within ClinicalTrials.gov Records 9. REGIST-202 (formerly SS-308): National Cancer Institute Clinical Trials Reporting Program (CTRP) 10. REGIST-300 (formerly QA-713): National Cancer Institute Investigator Registration a. Helpful Resource: NCI Financial Disclosure Form (FDF) b. Helpful Resource: NCI Statement of Investigator Form (Form FDA 1572) c. Helpful Resource: NCI Supplemental Investigator Data Form (IDF)

Research Start-Up (RSU) SOPs 1. RSU-100 (formerly SS-302): Site Qualification Visit by External Sponsors 2. RSU-101 (formerly SS-303): Site Initiation Visit by External Sponsors a. Helpful Resource: Sample Research Start-Up Checklist

R.10. Office for Human Research Studies Information Sheets http://www.dfhcc.harvard.edu/clinical-research-support/office-for-human-research-studies- ohrs/information-sheets/

OHRS Information Sheets: Guidance 1. IS - Guidance for Writing a Social-Behavioral Research Protocol 2. IS - Guidance - Guidelines for Writing a Specimen / Data Collection and Banking Research Protocol 3. IS - Guidance - Procedures for Monitoring the Consent Process 4. IS - Guidance - Statistical Guidelines for Non-Clinical Research 5. IS - Guidance - Withdrawal of Consent to Continue in Research Form

OHRS Information Sheets: Operations

1. IS - Operations - Common Issues in Protocol Reviews 2. IS - Operations - Completing Endorsement Forms 3. IS - Operations - Completing Nursing & Pharmacy Screening Form 4. IS - Operations - Completing the Protocol Front Sheet 5. IS - Operations - Frequently Asked Questions 6. IS - Operations - Guidance Priority List 7. IS - Operations - New Protocol Submission Requirement Chart 8. IS - Operations - Non Clinical FAQ 9. IS - Operations - OHRS Submit Guide 10. IS - Operations - OncPro Guide 11. IS - Operations - Overview DFCI IRBs 12. IS - Operations - PDF Files and Electronic Signatures 13. IS - Operations - Quick Reference for New Protocol Submissions 14. IS - Operations - Request to Add Site Checklist 15. IS - Operations - Review Process for New Adult Clinical Trials

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16. IS - Operations - Use of Informed Consent Documents Posted to OncPro

OHRS Information Sheets: Policy 1. IS - Policy - Adverse Event Reporting 2. IS - Policy - Blood Draws from Healthy Volunteers 3. IS - Policy - Collecting - Sharing Data and Tissue Specimens 4. IS - Policy - Continued Participation 5. IS - Policy - Determining if Project Is Human Subjects 6. IS - Policy - Deviation-Violation-Exception and Other Event Reporting 7. IS - Policy - DFCI IRB Requirements Relating to the Honest Broker in Biobanking 8. IS - Policy - Drug Shortages 9. IS - Policy - Implementing Dose Escalation Changes in Phase I Research 10. IS - Policy - IND and IDE Safety Reports 11. IS - Policy - Legally Authorized Representatives 12. IS - Policy - Linked and Anonymous Specimens 13. IS - Policy - Non English Speaking Subjects 14. IS - Policy - Overall PI or Site PI Leave of Absence 15. IS - Policy - Pregnant Partner Consent and Data Collection 16. IS - Policy - Prisoners in Research 17. IS - Policy - Sharing Protocols 18. IS - Policy - Short Form Translation Procedure 19. IS - Policy - Single Patient IND and Emergency Use of a Test Article 20. IS - Policy - Sponsor Requests for PHI related to Adverse or Severe Adverse Events 21. IS - Policy - Two Year CR 22. IS - Policy - Use of Alert Pages

OHRS Information Sheets: Resource 1. IS - Resource - Additional Protections for Children 2. IS - Resource - Adverse Event Ranking Scale 3. IS - Resource - Common Language for Drug Risks 4. IS - Resource - Common Language for Risks and Events 5. IS - Resource - Criteria for IRB approval of Research 6. IS - Resource - Expedited and Exempt Categories 7. IS - Resource - FDA Drug Review Process 8. IS - Resource - FDA Guidance Recruitment 9. IS - Resource - FDA Medical Devices 10. IS - Resource - How to contact the FDA 11. IS - Resource - Massachusetts Law on Insurance Coverage 12. IS - Resource - MSWord Tips 13. IS - Resource - Partners Recruitment of Subjects 14. IS - Resource - Requirements for Informed Consent 15. IS - Resource - Successful Research Participation Communication

R.11. Additional Regulations and Standards:

1. FDA Electronic Records and Signatures (21 CFR Part 11) 2. FDA Informed Consent (21 CFR Part 50)

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3. FDA Child Safeguards (21 CFR 50 Subpart D) 4. FDA Financial Disclosure (21 CFR Part 54) 5. FDA Institutional Review Boards (21 CFR Part 56) 6. FDA/DHHS Expedited Review Categories 7. FDA Investigational New Drug Regulations (21 CFR Part 312 & 314) 8. FDA Biological Licensing (21 CFR Part 600) 9. FDA Investigational Device Regulations (21 CFR Part 812 & 814) 10. FDA Information Sheets on Medical Devices (FDA Guidance) 11. DHHS Human Subject Regulations (45 CFR Part 46) 12. DHHS/FDA Expedited Review List 13. DHHS Emergency Research Consent Waiver 14. DHHS Misconduct in Science Regulations (42 CFR Part 50 Subpart A) 15. DHHS Objectivity in Research Regulations (42 CFR Part 50 Subpart F) 16. Financial Relationships and Interests (HHS Guidance) 17. Fetal Tissue Transplantation Research (Public Law 103-43) 18. Engagement of Institutions in Research (OHRP Guidance) 19. Non-English Short Form Consent (OHRP Guidance) 20. Data & Tissue Repositories (OHRP Guidance) 21. Inclusion of Children & Women and Minorities in Research (NIH Guidance) 22. Good Clinical Practice: FDA Guidance – ICH-GCP-E6

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