Columbia University Institutional Review Board Standard Operating Procedures, Study notes of Medical ethics

Download Columbia University Institutional Review Board Standard Operating Procedures and more Study notes Medical ethics in PDF only on Docsity! COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK Institutional Review Board Standard Operating Procedures Version 5.2: Effective February 12, 2019 (posted online September 12, 2019) Version 5.1: Effective April 12, 2018 Version 5.0: Effective December 21, 2017 1 Columbia University Institutional Review Board Standard Operating Procedures Version 5.2 February 12, 2019 Versions 5.1 4/12/18; 5.0 12/21/17 Table of Contents Introduction to the Columbia Human Research Protection Program 8 I. Human Research Protection Program (HRPP) 15 A. Institutional Review Boards and Human Research Protection Office (HRPO) 15 1. HRPO Administrative Staff 16 a. Organization 17 1) Administrative Support to Review Panels 17 2) Compliance Oversight Team 17 b. Duties 18 c. Education and Training 18 d. Confidentiality and Conflict of Interest 19 2. Committees within the IRB Office 19 a. Education and Training Committee 19 b. Policy Committee 19 c. Accreditation Committee 19 d. Rascal Committee 19 B. Privacy Board 20 C. Office of Sponsored Projects Administration 20 D. Clinical Trials Office 20 1. Research Pharmacy 21 2. IND/IDE Assistance Program 21 3. Clinical Trials Monitoring Assistance Program 21 4. Spanish Translation Center 21 5. Departmental Quarterly Monitoring Program 22 E. Office of Research Compliance and Training 22 F. Joint Radiation Safety Committee, Radioactive Drug Research Committee, and the Radiation Safety Office 22 G. Institutional Biosafety Office 23 H. Protocol Review and Monitoring Committee 23 I. Irving Institute for Clinical and Translational Research 24 J. NYP Pharmacy 24 K. NYP and Columbia Doctors Patient Services Administration/Office 24 L. Center for Bioethics 24 M. Department Chairs, Investigators, and Departmental Administrators 25 II. Institutional Review Boards 26 A. Columbia IRBs and Administrative Review Committee 26 1. Guiding Principles, Regulations, Statutes, Standards, Policies 26 2. Structure 26 3. Scope of Authority 27 4. Autonomy 28 5. Research Conducted by Columbia Faculty, Employees, and Students 28 2 1. Notification: Approval and Outcome of Review 92 2. Notification: Disapproval 92 3. Notification: Suspension and/or Termination 93 F. Documentation of Review and Approval 93 V. IRB Pre-review and Review Criteria 95 A. Pre-review of Submitted Events 96 1. Pre-review: New Protocols 96 2. Pre-review: Renewals (Continuing Review) 98 3. Pre-review: Modifications 100 4. Pre-review: Unanticipated Problem Reports 100 5. Pre-review: Closure Requests 101 B. IRB Criteria for Approval of Research 101 1. Risks to Subjects are Minimized (applies the principle of beneficence) 102 2. Risk/Benefit Ratio is Acceptable (applies the principle of beneficence) 104 3. Selection of Subjects is Equitable (applies the principle of justice) 105 4. Informed Consent Process is Appropriate (applies the principle of autonomy) 105 a. Special Consent Situations 108 1) Consent from Non-English Speaking Subjects 108 2) Consent for Audio- and Video Recording 108 3) Consent for Live Case Procedures 108 4) Same Day Consent for Elective Procedures 109 5) Consent from Women in Labor 110 6) Enrolling Illiterate Subjects 110 7) Enrolling Individuals with Physical Limitations Related to Writing 110 8) Obtaining Consent for Future Use of Specimens 111 9) Obtaining Consent for Future Contact for Research 111 10) Electronic Informed Consent 111 b. Waiver of Some or All of the Elements of Informed Consent 112 5. Documentation of Informed Consent is Appropriate (applies the principle of autonomy) 114 6. Data and Safety will be Monitored (applies the principle of beneficence) 115 7. Privacy & Confidentiality will be Protected (applies the principle of beneficence) 117 8. Recruitment Methods and Advertising Material are Appropriate (applies the principles of autonomy and justice) 119 9. Additional Protections are in Place for Vulnerable Subjects (applies the principle of beneficence) 121 10. Potential Conflict of Interest of Investigators and the Institution is Eliminated, Mitigated or Managed 122 VI. IRB Review of Specific Events, Types of Research, and Types of Documents 125 A. IRB Review of Specific Events 125 1. Initial Review (Review of a New Protocol) 125 2. Review of Modifications 127 3. Review of Reports of Unanticipated Problems Involving Risks to Subjects or Others 129 4. Review of Reports of Protocol Deviations or Violations 130 5 5. Review of Emergency Use Requests 131 a. Initial Notification to the IRB 132 b. Consent Requirements for Emergency Use of a Test Article 132 c. Documentation Required 133 6. Facilitative Review 134 7. Continuing Review (Renewal) 134 a. Continuation Past Expiration of IRB Approval 137 b. Procedures for Determining Which Projects Require Review More Often than Annually 137 8. Review of Closure Requests 138 9. Suspension and IRB-initiated For-cause Termination of Research 138 B. Review of Specific Types of Research 140 1. Review of Research Involving Investigational Drugs and Biologics 140 2. Review of Research Involving Medical Devices 141 3. Review of Humanitarian Use Devices 143 4. Review of Research Involving Pregnant Women, Neonates, and Fetuses (45 CFR 46, Subpart B) 145 5. Review of Research Involving Prisoners (45 CFR 46, Subpart C) 146 6. Review of Research Involving Children (45 CFR 46, Subpart D) 149 7. Review of Research Involving Other Vulnerable Adults 154 8. Review of Research Involving Non-English Speaking Subjects 155 9. Review of Research Involving International Sites 156 10. Review of Planned Emergency Research 160 a. Exception from Informed Consent 161 11. Review of Research that involves Human Embryonic Stem Cells 164 12. Review of Research Conducted by Students 164 13. Review of Research that is Federally-supported or -conducted, or is Otherwise Subject to Federal Policy 165 C. Review of Specific Types of Documents 165 1. Review of Recruitment Material 165 2. Review of Funding Documentation 168 3. Review of Investigational Drug Brochure 168 4. Review of Payments to Participants 168 VII. IRB Convened Meetings: Organization and Management 170 A. Schedule of Meetings 170 B. Agenda Preparation 170 C. Primary Reviewer Assignments 170 D. Voting Requirements 170 E. Minutes 171 1. Recording of Minutes at the Convened Meeting 171 2. Approval of Minutes 173 3. Notification of IRB Action 174 4. Appeal of IRB Decision 174 VIII. Record Retention and Documentation 175 A. Records Maintained 175 B. IRB Files 176 C. Record Retention Term 177 1. Research Records 177 6 2. IRB Records 177 D. Procedures if PI Leaves Columbia 178 E. Inspection of Records 178 F. Off-site Storage of IRB Files 178 IX. Oversight Monitoring 180 A. Renewal (Continuing Review) 180 B. Review of Unanticipated Problems Involving Risks to Subjects or Others (Including Adverse Events) 181 C. Data and Safety Monitoring 181 D. Reviews or Monitoring by the Research Pharmacy, Radiation Safety Committees, or Institutional Biosafety Committee 181 E. Reviews by Research Administration Offices 182 F. Compliance Oversight 182 X. Education and Training 185 A. Research Community 185 B. Board Members and Chairs 186 C. Administrative Staff 188 D. Researchers 189 XI. Quality Assurance and Improvement 192 A. Assessment and Improvement Initiatives of Internal Processes 192 B. Assessment and Improvement of External Processes 193 XII. Subject Outreach 194 A. Information for Potential Subjects 194 B. Information from Research Subjects and the Community 194 C. Compliance Hotline 195 D. IRB Education and Review 196 E. Evaluation of Outreach Efforts 196 Appendix I: Abbreviations and Terms 198 A. Alphabetical Order 198 B. In Order of Appearance 201 Appendix II; Referenced Regulations, Laws, Standards 205 Appendix III: Chronology 206 7 Introduction Page Intro - 3 IRB SOP V5.1 – April 12, 2018 Essential to the success of the Columbia HRPP is the institutional culture or conscience that permeates all components of the program. Research is one of the key missions of Columbia, which prides itself on its commitment towards excellence in all research activities. Columbia and NYP recognize that the ethical conduct of research is not only vital for the success of the research enterprise and the public trust in our research programs, but more importantly, that the institutions have a moral responsibility to act accordingly. Towards these ends, the EVPR and the IOs of CUIMC and NYP lead the Columbia HRPP in many different ways, including: 1) instilling the above described culture; 2) supporting the Columbia HRPP with the necessary funds, resources, and intellectual support; and 3) providing the necessary authoritative leadership and support for ensuring the integrity of Columbia’s program for the handling of alleged noncompliance incidents. Evaluation of resources needed for the HRPP is conducted at least annually and includes consideration of the needs of all components of the HRPP that are under the purview of the EVPR. In conjunction with the VPRO, leadership within each research administrative office considers the requirements of their respective unit in terms of personnel, space, equipment, and any other factor relevant to attainment of unit goals. In addition, resources required to maintain regulatory review committees, including IRBs, radiation safety committees, and the institutional biosafety committee, are evaluated at least annually. Financial and other resources needed to ensure adequate education and training activities for members of the research community and administrative personnel, production of handbooks and other university-wide research tools, quality assurance and improvement activities for the entirety of the research program, and maintenance of the Office of the EVPR are also routinely evaluated. The EVPR and VPRO assess the support received from University and external legal counsel, and other offices that provide research-related services throughout the University, in terms of availability, expertise, and adequacy to meet the needs of research- related offices and functions. C. Standard Operating Procedures 1. Development Columbia University has adopted these Standard Operating Procedures (SOPs) to ensure the ethical conduct of research and the protection of the rights and welfare of human subjects participating in research conducted under the authority of the University. These procedures describe the means by which research with human subjects will be reviewed, approved, and monitored. The IRB SOPs comply, where applicable, with the U.S. Department of Health and Human Services (DHHS or HHS) and the U.S. Food and Drug Administration (FDA) regulations on research with humans. The written procedures also comply with the International Conference on Harmonization (ICH) “Guidance for Industry- E6 Good Clinical Practice: Consolidated Guideline,” to the extent that they are consistent with federal law and regulations, 10 Introduction Page Intro - 4 IRB SOP V5.1 – April 12, 2018 Review of protocols supported or conducted by other federal agencies, such as the Department of Defense (DoD), Environmental Protection Agency (EPA), U.S. Department of Education (DOE), U.S. Department of Energy (DOEn), and the National Institutes of Justice (NIJ), includes consideration of compliance with the agency’s regulations for the protection of human subjects. Similar considerations are made for research that is subject to additional federal policies, e.g., conducted within facilities under the purview of the Bureau of Prisons, subject to the Family Educational Rights and Privacy Act (FERPA), or subject to the Protection of Pupil Rights Amendment (PPRA). Policies and procedures are developed within the IRB by one of the two standing committees described in Section I.A.3: the Policy Committee or the Accreditation Committee, or otherwise as necessary, under the direction of the ED. The IRB SOPs will be reviewed regularly. Any necessary revision to these policies must be made through the process described in the following section. 2. Process for Revising Standard Operating Procedures a. A proposed revision to an SOP must be submitted to either the Policy or Accreditation Committee for consideration. 1) More significant changes that may have broader implications should be handled by the Policy Committee. 2) Minor or less significant changes can be handled by the Accreditation Committee. b. If necessary, the Chairs of each Committee discuss jurisdiction of any proposed revision and decide which Committee will consider the revision. The ED has the authority to make the final decision. c. Once a proposed revision is considered by either Committee, a draft is forwarded to the ED, and the relevant Director(s), Assistant Director, Senior Manager(s) and, when appropriate, to all IRB Chairs, the VPRO and staff for review and consideration. After a designated review period, all comments are considered by the Committee that drafted the proposed revision. 1) If no substantive changes have been made during the review period, the final draft version is forwarded to the ED for approval. Approval of revised policies is documented with signoff by the ED. 2) If substantive changes are made during the review period, a revised version is again circulated as described above. This process continues until the final revised policy is approved. The ED has the authority to revise and approve the policy at a point when all remaining concerns are editorial or grammatical, the need to release a new or revised policy is time-sensitive or the process is not moving forward. 11 Introduction Page Intro - 5 IRB SOP V5.1 – April 12, 2018 3) As necessary or appropriate, draft policies are circulated between CU and NYP, and to other individuals or entities within the institution, e.g., Office of the General Counsel (OGC), EVPR, Office of Research Administration, which includes the Clinical Trials Office (CTO), Sponsored Projects Administration (SPA), and the Office of Research Compliance and Training (RCT). d. Approved policies and changes to these SOPs are announced via the CU HRPO/IRB listserv, at a minimum, and posted on the CU HRPO website. Appropriate individuals (e.g., research personnel, HRPO staff, IRB members and Chairs, VPRO, IOs, EVPR) are notified of new policies and changes to these written procedures. Revisions to the SOPs may be made on a section or item basis. This process allows more timely updates to an SOP rather than requiring re-approval of all SOPs with each revision. At the discretion of the ED or the relevant Director, any change to the SOPs may be implemented immediately without following this process if a determination is made by the ED or the relevant Director that the change is necessary for the immediate protection of human subjects or to address an urgent regulatory compliance concern. D. Requirement for Submissions All protocols for human subjects research to be conducted by Columbia faculty, employees, and students must be submitted for review in Rascal, Columbia’s research administration and compliance Information Technology (IT) system. Non-exempt projects must be prospectively approved by the appropriately designated IRB under one of Columbia’s FWAs or by an IRB to which Columbia has ceded IRB review through the terms of a reliance agreement. Exempt determinations at CUIMC are made by an Administrative Review Committee (ARC) within the IRB office or any IRB Chair or Vice Chair; at CU-MS, exempt determinations are made by the IRB Chair or Vice Chair. It is a Columbia policy that investigators may not make the final determination of exemption, i.e., protocols that appear to meet federal criteria for exemption must be submitted in Rascal for confirmation of exempt status. Certain pedagogical activities conducted by students must also be submitted for review, in accordance with the IRB Students as Researchers Policy (Reference Document #304), even though the regulatory definition of research may not be met. E. Definitions of Research and Human Subject Throughout these written procedures, “human subjects research” (HSR) is defined as those activities that meet the criteria articulated in applicable U.S. DHHS regulations to be considered as both “research” and as involving “human subjects.” Research: a systematic investigation, including research development, testing and evaluation, designed to develop or contribute to generalizable knowledge. Activities which meet this definition constitute research for purposes of this policy, whether or not they are conducted or supported under a program which is considered research for 12 Section I: Human Research Protection Program Page I - 1 IRB SOP V5.0 – Dec. 21, 2017 I. Human Research Protection Program (HRPP) A brief overview of the Columbia HRPP is provided below. A. Institutional Review Boards and Human Research Protection Office (HRPO) The mission of the CU IRBs and the CU HRPO, which form the core of the Columbia HRPP, is to enhance and facilitate the ethical conduct of human subjects research that is conducted: a) at Columbia; b) through the support of Columbia funding; and/or c) by Columbia faculty, and other Columbia and NYP researchers, regardless of location of the research. The CU IRBs perform this mission through their review of human subjects research, and are supported in this endeavor by the HRPO educational and training initiatives, and compliance oversight and quality improvement programs. The IRBs are not solely responsible for the integrity and conduct of such research, nor are they responsible for the programmatic development or decisions as to what research should or should not be conducted at Columbia. These considerations also fall under the purview of the Dean of CUIMC, the President of NYP, and the EVPR, each of whom have the authority to restrict research that cannot be supported by resources, principles, or policies of their respective institutions, regardless of whether it has been approved by one of the CU review panels. Columbia review boards and those of other institutions play a crucial role in the effective protection of the human subjects who are involved in research that comes under the purview of the HRPP. A detailed description of the Columbia IRBs, including scope of authority, constitution, organization, membership, and use of consultants, and an explanation of the role that non-Columbia IRBs fulfill for the HRPP, is provided in Section II. The HRPO is the central administrative office for the Columbia HRPP. This office serves as the central repository of all information affecting the protection of human subjects in research. The HRPO is responsible for the management and oversight of all IRBs at CU-MS and CUIMC. In addition, the HRPO is responsible for ensuring that all relevant information affecting the safety and welfare of human subjects in research, and noncompliance issues, are reported to the IRBs, and as appropriate to the IOs, federal regulatory agencies, sponsors, and AAHRPP. Leadership within the HRPO is a team that consists of the ED, the Directors in the areas of Operations, IRB Management and Compliance Oversight and the Assistant Director for IRB Management (collectively, D/ADs) that works closely with the managers of the teams that directly support the IRBs. The HRPO has two locations: a) on the CUIMC campus, and b) on the Manhattanville campus, (see Reference Document #160, IRB Contact Information, for current addresses). The HRPO convenes ad-hoc meetings that involve the heads of other HRPP units as necessary to address any incidents or issues that may require consideration from or action by one or more of those units. As warranted, the ED or other director sends communications of 15 Section I: Human Research Protection Program Page I - 2 IRB SOP V5.0 – Dec. 21, 2017 relevant information regarding the ethical conduct of human research and the protection of human subjects to all heads of Columbia HRPP units. The ED participates in monthly meetings that are convened by the EVPR and include the heads of all units under his authority. The ED also leads twice monthly meetings of the IRB Executive Committee (IEC). This Committee is comprised of the Chairs and Vice Chairs of all IRBs, the VPRO, the ED, and the D/ADs. The purpose of these meetings is to improve the quality and consistency of the work performed by the IRBs and to address overarching issues and challenges that may face the collective IRBs. Managers and Assistant Managers are encouraged to attend IEC meetings. When agenda items warrant, all IRB officers are also encouraged to attend this meeting. Four other committees within the IRB office support initiatives to improve the ethical conduct and review of research: 1) Education and Training Committee; 2) Policy Committee; 3) Accreditation Committee; and 4) Rascal Committee. The purpose of each committee is discussed in more detail below (Sections I.A.3.a-I.A.3.d). Additional committees may be constituted as necessary to support office initiatives. 1. HRPO Administrative Staff The ED maintains overall responsibility for the management of all CU IRBs and the HRPO staff. Oversight of the performance and management of specific areas have been delegated to the D/ADs:  IRB Operations to the Director for Operations (DO), who reports to the ED  Day to day activities of all CU IRBs to the Director for IRB Management (DIM), who reports to the ED and to whom the Assistant Director for IRB Management (ADIM) reports. Each IRB Chair and IRB Manager are responsible for the daily management of their respective Board;  Compliance Oversight to the Director for Compliance Oversight (DCO), who reports to the ED. The HRPO provides sufficient professional and administrative support, and adequate resources, to ensure compliance with federal and state regulations and institutional policies for the protection of human subjects in research. The commitment of staffing resources for the HRPO is evaluated internally on an ongoing basis by the ED and D/ADs, with input from the IRB Managers, as applicable, and additional support is provided as needed. Through regular meetings with the VPRO and CUIMC IO, the ED communicates office-wide requests for additional support as warranted. Adequate meeting and office space are provided for the IRBs and HRPO staff. Office equipment and supplies, including file cabinets, computers with Internet access, and copy machines, are available to the HRPO staff. 16 Section I: Human Research Protection Program Page I - 3 IRB SOP V5.0 – Dec. 21, 2017 a. Organization 1) Administrative Support to Review Panels Each IRB is administered by a team of staff comprised of a senior HRPO staff member, who will generally be a Manager or Senior Manager, and at least one other officer. A Senior Manager may oversee more than one IRB or review committee, or have defined office-wide responsibilities in addition to managing a team that supports a specific IRB. Each team is responsible for: a) ensuring that all research reviewed by its IRB is in compliance with all applicable standards and that all reviews are handled efficiently and at a high level of quality; b) providing its IRB members with the necessary information to conduct their reviews; and c) preparing all communications to the research teams whose submissions have been reviewed. Submissions (i.e., new protocols, modifications, renewals, reports of unanticipated problems, and closure requests) are triaged upon receipt and undergo a thorough administrative, preliminary review (“pre-review”) utilizing a detailed pre-review form or review template based on the type of submission. The pre-review process is designed to help ensure that each submission is complete and can proceed for review by an IRB member or, in the case of CUIMC exempt research, an HRPO officer, and that each study will receive all relevant regulatory considerations. Once a study has undergone a pre-review, it proceeds to an IRB (for CUIMC non-exempt and all CU-MS studies) or to the ARC or a Chair (for CUIMC exempt studies) for review. 2) Compliance Oversight Team The Compliance Oversight Team (COT) is comprised of the DCO and auditors. The COT is responsible for investigating, managing and tracking all allegations of serious and/or continuing noncompliance, concerns about research conduct, and complaints with respect to the protection of human subjects in research, and tracking all other allegations and incidents of noncompliance. Allegations of noncompliance, concerns, or complaints may be received from anyone, e.g., the IRBs, HRPO staff, faculty, research staff, IOs, departmental administrators, research subjects, federal and state regulatory agencies, the media, or the general public, and may be reported anonymously. All such allegations, concerns and complaints, as well as any event that must be reported to federal regulatory agencies (e.g., serious and/or continuing noncompliance, certain unanticipated problems, and suspension of IRB approval) are logged by the COT into a database for tracking and reporting purposes. The DCO keeps the ED informed of all cases through regular meetings and reports. The COT also works with the Office for HIPAA Compliance (OHC) regarding any concern or finding of research noncompliance with the Health Insurance Portability and Accountability Act (HIPAA). 17 Section I: Human Research Protection Program Page I - 6 IRB SOP V5.0 – Dec. 21, 2017 The Rascal Committee was established in 2004 within the HRPO and is charged with working with the Rascal IT Team for further development and enhancement of the Rascal system as it relates to the Human Subject and Consent Form modules. The Rascal Committee is the central repository of all suggestions for improvement of the IRB module. The Committee is responsible for prioritizing all requests for Rascal improvements with the input of the IRB Chairs and staff. Meetings are held on an ad- hoc basis as necessary to accommodate the current needs of the Rascal system and evaluate any new processes being tested. The Committee is chaired by an experienced officer on the HRPO staff, and is comprised of HRPO staff. An executive subcommittee consisting of the ED and DO meets regularly with the Rascal development team. B. Privacy Board The Columbia University IRBs serve as the Privacy Boards for the review of protected health information that may be used by Columbia investigators, and for ensuring compliance with the HIPAA Privacy Rule. The implementation of policies and processes to ensure such compliance is the responsibility of the Chief Privacy Officer (CPO), who directs the Office of HIPAA Compliance and reports to the Billing Compliance Officer within the Office for Billing Compliance (OFBC). The CPO coordinates such efforts with the ED and/or D/ADs of the HRPO, and the COT. See Reference Document #115 (CU IRB Policy on Research and the HIPAA Privacy Rule) and Reference Document #116 (CUIMC IRB Procedures to Comply with Privacy Laws that Affect Use and Disclosure of Protected Health Information for Research Purposes) for additional information. C. Office of Sponsored Projects Administration SPA, together with the CTO described below, is responsible for the administration of all sponsored research conducted by Columbia. SPA works closely with the HRPO staff to ensure that all such human subjects research has obtained appropriate IRB approval prior to creation of an account for research funding and prior to execution of any data sharing or material transfer agreements. Any potential noncompliance with the regulations for human subjects protection that is identified by a SPA staff member is promptly reported to the ED and/or the DCO. D. Clinical Trials Office The CTO is responsible for the administration of all clinical trials conducted by the Vagelos College of Physicians and Surgeons. The CTO fosters the ethical conduct of research by establishing important provisions and policies that are relevant for the protection of human subjects. For example, in its contract negotiations, the CTO addresses issues such as ensuring prospective IRB review, payment for research procedures and test articles, compensation for research related injuries, and the protection of confidentiality of research data. Any potential noncompliance with the regulations for human subjects protection that is identified by a CTO staff member is promptly reported to the ED and/or the DCO. The CTO also administers the Research Pharmacy (RP), the Investigational New Drug 20 Section I: Human Research Protection Program Page I - 7 IRB SOP V5.0 – Dec. 21, 2017 (IND)/Investigational Device Exemption (IDE) Assistance Program (IAP), the Clinical Trials Monitoring Assistance Program for FDA Regulated Human Subjects Research (CTMAP), Clinical Research Coordinator Training (CRCT), and the Spanish Translation Center (STC). The CTO also manages the Departmental Quarterly Monitoring Program. 1. Research Pharmacy The RP is responsible for the storage, handling, accountability, and dispensing of investigational drugs to research investigators. The RP is overseen by the CTO, and research pharmacists may serve on one or more of the CUIMC IRBs. The close working relationship between the RP and the IRB not only provides pharmacy input to the IRBs, but also helps to ensure that the handling of investigational drugs is in compliance with federal and state regulations as well as institutional and IRB policies. Any potential noncompliance with the regulations for human subjects protection that is identified by the RP is promptly reported to the ED and/or the DCO. 2. IND/IDE Assistance Program The IAP was established in 2010 to assist, at all stages of a clinical investigation, Columbia investigators who hold an IND or IDE. The IAP provides the following services to the research community: guidance and education to investigators regarding the responsibilities of sponsors of INDs or IDEs; guidance in the preparation of all documents submitted to the FDA; assistance in the maintenance of an IND or IDE; and consultation in all regulatory matters. The IAP and HRPO have developed institutional policies to assist investigators implement an effective IND or IDE for their research. Any potential noncompliance with the regulations for human subjects protection that is identified by the IAP is reported to the ED and/or the DCO. 3. Clinical Trials Monitoring Assistance Program The CTO has established a program to assist Sponsor-Investigators (S-Is) in meeting FDA requirements with respect to monitoring of S-I studies. From the design and development of a monitoring plan to periodic review of adherence, assistance to Columbia faculty and clinical research coordinators is available from CTMAP. Details of the Program are available on the CTO website and in the Clinical Research Handbook. 4. Spanish Translation Center The STC provides translation into Spanish of research documents such as consent forms, recruitment letters, and advertisements for potential research subjects. The STC serves a vital role in Columbia’s human research protection program because CUIMC and NYP are located in a community with a predominantly Hispanic population, many of whom are non-English speaking. The STC works with the IRB to fulfill requirements of the IRB Enrollment of Non-English Speaking Subjects in Research Policy (Reference Document #101). Any document that will be translated by the STC or other acceptable translation options must first be approved in English by the IRB. Final approval by the 21 Section I: Human Research Protection Program Page I - 8 IRB SOP V5.0 – Dec. 21, 2017 IRB of translated document(s) is granted after review and approval of the translated document certified by the STC or accompanied by a certification of accuracy by another translator. Any potential noncompliance with the regulations for human subjects protection that is identified by the STC is promptly reported to the ED and/or DCO. The STC was previously known as the Hispanic Translation Center; reference to the Center by this name may be found on historical documents and in the STC approval stamp. 5. Departmental Quarterly Monitoring Program On a quarterly basis, departments are required to provide a report of the monitoring of clinical research that has been conducted during the preceding quarter. Each department or, in the case of smaller departments, a group of departments, has a designated monitor who conducts the reviews and generates a report that is provided to the research team, department and the CTO. Summaries of the reports are generated by the CTO and distributed to designated institutional representatives including the Senior Vice Dean, the General Counsel, the VRPO, the Vice President for Research Administration, and the ED. E. Office of Research Compliance and Training RCT develops and provides certain educational training initiatives for Research Administration Offices that do not have their own education training program, or to supplement other training. RCT works with the Columbia HRPO on an ad hoc basis to complement the educational training initiatives of the HRPO. RCT also provides certain compliance oversight efforts. One such effort is to manage any noncompliance involving research integrity (i.e., fabrication, falsification, or plagiarism). RCT also provides administrative assistance to, and works closely with, the CUIMC Conflicts of Interest (COI) Committee in accordance with Columbia’s COI policy. All Columbia officers must complete a COI form when they are hired and must update this form annually. In addition, all Principal Investigators, co-Investigators, and other key personnel on human research proposals must complete a protocol-specific conflict of interest form prior to submission of a research study for IRB approval. The Rascal system facilitates the management of conflicts of interest by identifying any positive response for conflicts in either the Columbia annual COI disclosure statement or the protocol specific COI form. RCT works closely with the Columbia IRB office to foster the ethical conduct of research at Columbia. F. Joint Radiation Safety Committee, Radioactive Drug Research Committee, and the Radiation Safety Office The Joint Radiation Safety Committee (JRSC) oversees the radiation safety program for CUIMC, CU-MS, NYP, and New York State Psychiatric Institute (NYSPI). The JRSC, in accordance with New York City (NYC) regulatory requirements, oversees the use of all sources of radiation and licensed radioactive material, whether for research or clinical 22 Section I: Human Research Protection Program Page I - 11 IRB SOP V5.0 – Dec. 21, 2017 educational training conferences and seminars in the area of bioethics. In 2018 the Center’s role will be taken on and expanded by the new Department of Humanities and Medical Ethics at CUIMC currently under development. M. Department Chairs, Investigators, and Departmental Administrators Department Chairs and Investigators are responsible for ensuring that all research involving human subjects is conducted in accordance with ethical principles, institutional policies, and federal and state regulations. The leadership provided by the Department Chairs, Investigators, and Departmental Administrators helps to ensure that research at Columbia is conducted with high quality and in an ethical manner. The research investigators and staff are at the forefront of human research protections, as they are best positioned to directly ensure that research is conducted ethically. Principal Investigators (PIs) have particular responsibility for conducting research in accordance with the approved protocol and in such a manner that subjects are protected to the extent possible. Additional information relating to PI eligibility, roles and responsibilities, and training is provided in Section III.C and X.D. Department Chairs are notified whenever serious and/or continuing noncompliance with human subject research policies or regulations occurs within their department. Likewise, any potential noncompliance with the regulations for human subjects protection that is identified internally is promptly reported to the ED and/or the DCO. 25 Section II: Institutional Review Boards Page II - 1 IRB SOP V5.2 – February 12, 2019 II. Institutional Review Boards A. Columbia IRBs and Administrative Review Committee 1. Guiding Principles, Regulations, Statutes, Standards, Policies All CU IRBs are governed by the principles of the Belmont Report, applicable statutes, standards, and policies, and the federal regulations for the protection of human subjects in research as codified by: a. the U.S. DHHS regulations, 45 CFR Part 46, Subparts A (Common Rule), B, C, D and E; b. the U.S. FDA regulations, 21 CFR Parts 50, 56, 312, 600, and 812; c. the Department of Education (DOE) regulations 34 CFR 97 including the Family Education Rights and Privacy Act (FERPA), 34 CFR 99, the Protection of Pupil Rights Amendment, 34 CFR 98, and the National Institute for Disability and Rehabilitation Research, 34 CFR 350; d. the U.S. Department of Defense (DoD) regulations and DoD Directive (DoDD) 3216.02; e. the U.S. Environmental Protection Agency (EPA) regulations, 40 CFR 26, Subpart A; f. the U.S. National Institute of Justice regulations, 28 CFR 46; g. the U.S. Department of Justice, Bureau of Prisons regulations, 28 CFR 512; h. the U.S. Department of Energy (DoEn) regulations, 10 CFR 745; i. New York State Public Health Law Article 24-A (Protection of Human Subjects) and Civil Rights Law Article 7, Section 79-1 (Confidentiality of Genetic Tests); j. the HIPAA Privacy Rule of 1996, 45 CFR 160 and 164; k. Columbia institutional policies; and l. the AAHRPP Accreditation Standards. The IRBs are subject to regulation by federal oversight agencies, including the FDA and the Office for Human Research Protections (OHRP). Other federal, state and local agencies may have authority to oversee specific aspects of individual research projects or the research program in general. 2. Structure 26 Section II: Institutional Review Boards Page II - 2 IRB SOP V5.2 – February 12, 2019 There are seven review panels in the Columbia HRPP. Six IRBs (commonly referred to as “Boards”) are responsible for the review of non-exempt human subjects research conducted by faculty, employees, and students at CUIMC and NYP, and one IRB is responsible for human research (exempt and non-exempt) conducted by faculty, employees, and students at CU-MS. Of the six CUIMC IRBs, one is designated to review cancer-related research that initially requires review at a convened meeting (also referred to as a “Full Board” review) (IRB 4), one is designated to review research for which next generation sequencing is the primary aim and that initially requires review at a convened meeting, as well as limited cancer-related research (IRB 5), and one manages all research that initially qualifies for expedited review (IRB Exp). Exempt research and projects that do not meet the regulatory definitions of research or human subject are reviewed at CUIMC by HRPO staff with sufficient expertise or by IRB Chairs; collectively they comprise the IRB ARC. Additional IRBs or specialized review committees may be added as necessary to ensure adequate and timely review of research proposals. 3. Scope of Authority All CU IRBs are charged with the responsibility of providing review, approval, and oversight monitoring to ensure that all human research under the auspices of the Columbia HRPP is conducted: 1) ethically; 2) in a manner that protects human subjects, and 3) in accordance with the above mentioned regulations, laws, policies, and standards. The Boards have the responsibility and the authority to:  review all human subjects research described in Section II.A.5. for prospective IRB approval;  review progress of non-exempt studies at least annually and more often when deemed necessary;  observe or have a third party, whom the Boards determine is qualified and appropriate, observe the consent process or any aspect of the research;  suspend or terminate approval of any study that has an unanticipated problem involving risks to human subjects or others, serious or continuing noncompliance with any federal regulation, or serious or continuing noncompliance with the requirements or determinations of the IRB; such actions will generally be determined at a convened meeting of the full Board with a quorum present and will be incorporated into the minutes of the meeting;  restrict any study it determines to warrant such action, including situations in which one aspect of a study fails to comply with federal regulations or Board requirements or determinations; and  review research that was initiated without IRB approval for compliance with federal and state regulations and/or institutional policy. 27 Section II: Institutional Review Boards Page II - 5 IRB SOP V5.2 – February 12, 2019 Each Board will be distinct and completely separate from the other Boards in that it will act independently on protocols assigned to it. If an issue affects more than one Board (e.g., an investigator with studies open under more than one Board is failing to comply with regulations), each Board may address the issue separately or defer the issue to the IEC. The ED and/or DIM will provide guidance in such situations. Each Board has its own Chair. The Chairs on the CUIMC campus are administratively responsible to the Senior Vice Dean, who is the IO at CUIMC, and to the EVPR; the Chair on the CU-MS campus is administratively responsible to the EVPR. The Chairs have direct access to the EVPR, IO-CUIMC (as applicable), and the Dean of CUIMC for discussion of IRB issues. The EVPR is responsible for providing adequate support and resources for the overall operation of the HRPO and all IRBs. Coordination of inter-Board activity is achieved by the IEC. a. Membership Each Board is constituted to meet the regulatory requirements mandated by DHHS and the FDA, and institutional needs, i.e., membership includes individuals with the necessary expertise to evaluate the type and volume of protocols submitted for review. Alternate IRB members and consultants may serve these roles in addition to regular IRB members. Among all CUIMC IRBs, consistent membership and involvement as a voting member by at least one nurse is supported. b. Qualification of Members The membership of each Board includes individuals with varying backgrounds who possess the appropriate professional competence to review the diverse types of protocols that are received or to provide awareness of considerations of the local community. Examples include: a) cardiologists are involved in the review of innovative cardiac surgery and device protocols; b) psychology faculty are assigned as reviewers or asked to consult on research procedures that may result in participant stress requiring intervention; and c) investigators who are experienced in the design and conduct of community-based participatory research are available to provide consultation during IRB review of such research protocols. Each IRB includes among its membership at least one individual who has no affiliation with CU (and no immediate family member with an affiliation with CU) other than his/her IRB membership, at least one scientist, and at least one non- scientist. One member may fulfill more than one requirement. There is at least one voting member at every meeting whose interests and background are primarily non- scientific (lay person). One IRB member may fulfill both non-scientific and unaffiliated criteria. In addition, each Board that reviews FDA-regulated products (drugs, biologics, and devices) has at least one member who is a physician present at meetings. 30 Section II: Institutional Review Boards Page II - 6 IRB SOP V5.2 – February 12, 2019 A prisoner advocate is on the roster for CUIMC IRBs 1, 2, 3, and Exp, and the CU- MS IRB, either as a full member or as an alternate who counts towards quorum and as a voting member for prisoner research only. When reviewing prisoner research, a majority of the IRB members have no association with the prison involved, apart from their membership on the IRB. Experienced IRB officers may serve as alternate members of the IRB but may not generally conduct expedited reviews, other than for those submissions that have been determined to qualify for administrative review. For example, Columbia policy for administrative approval of translated documents permits an IRB staff member to verify that the appropriate English version of a document is the basis for the translated documents, confirm that there is an attestation of accuracy, and review the qualifications of the translator. When such requests are submitted in Rascal as a modification, an experienced IRB officer who has been appointed as an alternate IRB member may review and approve the submission via the expedited review process. c. Membership Diversity Membership is selected to assure appropriate diversity, including representation by multiple professions, appropriate scientific disciplines and specialties, varied ethnic backgrounds, and both genders, and to include both scientific and non-scientific members. d. Alternate Members One or more alternate members exist for each regular (i.e., primary) member of each IRB. Such alternate members must be of the same category of membership (i.e., scientific or non-scientific), and meet the afore-mentioned guidelines. Alternate scientific members need not be of the same discipline as the primary member(s) for whom they may serve. Alternate members may be necessary for quorum purposes or to provide requisite expertise. Use of alternate members for quorum purposes is separate from review assignments, which are based on area of expertise. e. Use of Consultants The Boards may, at their discretion, invite individuals with specific expertise or experience to assist in the review of complex issues that require expertise beyond or in addition to that available on the Boards. Consultants may provide their assessment and recommendation to the Board in written format, participate by tele- or videoconference, or attend the convened meeting. If participating in the meeting, these individuals may not vote with the Boards, unless they are appointed as an alternate to the respective Board and are serving in that capacity for a regular Board member. 31 Section II: Institutional Review Boards Page II - 7 IRB SOP V5.2 – February 12, 2019 Consultants will be required to sign a Confidentiality/Conflict of Interest Statement (Reference Document #76). Conflict of Interest information, including current policies, definitions of “financial interest” and “family member”, and disclosure forms, may be found on the “Conflict of Interest and Research” page of the RCT website. Efforts are made to select consultants who do not have a conflict of interest with the issue being considered. If present at the meeting or participating by tele- or videoconference, the Board may ask consultants questions related to the protocol prior to completion of the discussion, after which the consultant will disconnect the call/connection or leave the room for the remainder of the discussion and vote. When consultants are utilized, the terms of the service that will be provided, description of deliverables (e.g., written report, verbal presentation, review of investigator responses), and explanation of confidentiality agreements (e.g., whether name of consultant will be provided to the PI, whether the consultant’s report will be released to the PI, whether the PI may contact the consultant) should be documented in writing. Consultants will usually be identified by the respective Chair or HRPO staff, although in some cases, the PI or his/her department may be asked to suggest an individual with appropriate expertise. A list of consultants will be maintained by the HRPO. 7. Appointments, Terms, and Responsibilities of IRB Chairs, Vice Chairs, Members, and Alternates a. Chair/Vice Chair 1) Selection and Appointment The IO listed on the CUIMC or CU-MS FWA, as applicable, appoints the Board Chairs and Vice Chairs, after consultation with the ED, DIM and/or DO, and for Vice Chairs, the relevant IRB Chair. CU faculty who are Officers of Research or Officers of Instruction, and have sufficient expertise and experience, will be considered for these IRB positions. Other experienced IRB members will be considered on a case by case basis, taking into account their expertise and suitability for the position. A curriculum vitae will be required upon appointment, and a request for an updated version will be made periodically by the IRB. An appointment memo is prepared by HRPO staff for approval and signature of the appropriate IO. Copies of the signed memo are sent to appropriate individuals, including the IO, ED, DIM, DO, ADIM when relevant, and Manager of the relevant IRB. A copy is retained in the IRB member file. A letter that documents the appointment and describes member responsibilities is generated, signed by the ED, and sent to the appointee. Copies are sent to 32 Section II: Institutional Review Boards Page II - 10 IRB SOP V5.2 – February 12, 2019 All Board Chairs and Vice Chairs are required to sign a Confidentiality and Conflict of Interest Statement (Reference Document #76), the terms of which are reinforced during the orientation session. The statement also articulates the need and expectation for Board deliberations and details of the protocols that are submitted to the IRB to remain confidential. Chairs and Vice Chairs who have a real or perceived conflict of interest with a particular protocol, event, or issue that is reviewed by the Board must recuse themselves from relevant Board deliberations and may not participate in related voting. a) For convened meetings, this means that the Chair or Vice Chair may remain to answer relevant questions asked by the Board, but must leave the room during relevant Board deliberations related to decision, including the vote; the Chair will not count towards quorum for that review. HRPO staff, during preparation of the agenda for full Board meetings, will identify those submissions for which a Chair or Vice Chair who is expected to be in attendance has a conflict; this helps to ensure compliance with the need for any such members to leave the room during discussion of the protocol for which a conflict exists. If the conflicted Chair or Vice Chair is presiding over the meeting, this role would be covered, as previously described, during the discussion and vote. b) In the case of expedited reviews, a Chair who has a conflict of interest in relation to a specific protocol is expected to distribute the protocols to a different member or ask the Vice Chair to do so. HRPO staff who conduct the administrative review and identify a conflict will include that information in the Notes for the protocol. c) For both full Board reviews and expedited reviews, Rascal will not allow an individual who is named as Study Personnel on a submission or as an Approver to act in a Chair, member, or reviewer capacity. d) To the extent possible, IRB staff will not assign a protocol, for which an IRB Chair is the PI, to the IRB of which the PI serves as Chair. Conflict of Interest information, including current policies, definitions of “financial interest” and “family member”, and disclosure forms, may be found on the “Conflict of Interest and Research” page of the RCT website. b. IRB Members and Alternates 1) Selection and Appointment The Chairs and/or IO, in consultation with the DIM, DO and, when relevant, the DIM (or ED when necessary), recommend candidates for appointment as IRB 35 Section II: Institutional Review Boards Page II - 11 IRB SOP V5.2 – February 12, 2019 members and alternates, and the IO named on the FWA makes the appointment to the Board via signature on an appointment memo. Members and alternates will be selected in a manner that will ensure that all requirements of these IRB procedures and federal regulations are met. A curriculum vitae, which is generally reviewed during the recruitment process, will be required prior to appointment, and a request for an updated version will be made periodically by the IRB. A letter of appointment is prepared by HRPO staff for approval by the appropriate IO. Upon being signed, copies of the appointment memos and letters are distributed to appropriate individuals, including the IO, ED, DIM, DO, ADIM when relevant, and Manager of the relevant IRB. A copy is retained in the IRB member file. 2) Length of Term/Service Members and alternates are generally appointed to a term of up to three years, which may be renewed, and will be evaluated periodically (see Reference Document #114 for process). If a member or an alternate is appointed mid-term, his/her term will be calculated from the following July 1. Shorter terms may be considered in special circumstances. Board Members and alternates may be granted an extended leave due to medical, personal or professional reasons, then return to complete their term. IRB members and alternates are compensated for their service. In accordance with the “Recognition of Service by IRB Members” memo (Reference Document #127), IRB members and alternates will receive a token of appreciation upon completion of their service, or as otherwise determined. Recognition by other means (e.g., mid-term letters of appreciation for service, or appreciation events) may also be considered. 3) Duties Members and alternates (when serving as a voting member) independently evaluate project submissions that require full Board review prior to the IRB meeting, participate in appropriate discussions, and vote to approve, disapprove, defer to Chair or designee (i.e., require specific changes, Rascal status “pending”), defer to convened IRB (i.e., substantive revision required, Rascal status “return”), or table (i.e., review is postponed, Rascal status “defer”) each submission during the IRB meeting. These actions apply to: (a) initial reviews, (b) continuing reviews, (c) modifications (amendments), (d) reports of Unanticipated Problems involving Risks to Subjects or Others; and e) closure requests. Members and alternates (when serving as a voting member) also review and vote on other pertinent business, including compliance oversight activities, which is included on the agenda. 36 Section II: Institutional Review Boards Page II - 12 IRB SOP V5.2 – February 12, 2019 Experienced members or alternates may be assigned by the Chair or Vice Chair to review research activities that qualify for expedited review. An “experienced IRB member” means a voting member or alternate voting member who has received training relative to the expedited review categories and institutional policies governing human subjects research, and possesses the expertise needed to review the proposed research. 4) Attendance Requirements Members are usually provided with notice of meeting dates several months in advance and are expected to regularly attend meetings of the IRB to which they are appointed. Regular attendance for the unaffiliated member represents at least 75% of all convened board meetings. Members are expected to notify IRB staff affiliated with their respective IRB sufficiently in advance of known absences for the staff to substitute registered alternates, at the discretion of the Chair and Manager, whenever possible; use of an alternate member is a requirement if the absence will affect quorum. When a situation arises that will result in an unanticipated absence, the member is expected to notify the staff at the earliest opportunity. At the discretion of the Chair and in consultation with the relevant IO designated on the applicable FWA, excessive absences by a member, or a pattern of absences that affects the functioning of the Board (e.g., three consecutive, or frequent unscheduled), may result in removal. 5) Removal, Resignation Resigning members or alternates must notify the Board Chair and/or the ED, or designee of their intentions in writing. The DO (or ED) will notify the appropriate IO. Prior to the start of each fiscal year, the Chair of each IRB, in consultation with the ED, DIM, and ADIM when relevant, respective Vice Chair(s), and/or respective IRB Manager, may determine that the appointment of any regular or alternate member whose term is expiring should not be renewed. Members or alternates may be removed in mid-term by the IO designated on the applicable FWA, or the EVPR. Recommendations for removal by the Board Chairs, other members of the Board, investigators, or other university officials will be considered. Individual termination letters are prepared and signed by either the ED, or an IO. Once signed, copies are distributed to appropriate individuals, including the IO, respective IRB Chair, ED, DIM, DO, ADIM when relevant and Manager of the relevant IRB. A copy is retained in the IRB member file. 37 Section II: Institutional Review Boards Page II - 15 IRB SOP V5.2 – February 12, 2019  description of a funding agency’s determination of a reviewing IRB for all sites; and/or  consultation with IOs and/or the OGC. The agreement through which the reliance agreement is documented will describe the division of responsibilities between Columbia and the other institution. a. Reliance on a Non-Columbia IRB Prior to executing an IAA in which Columbia will rely on the review of another IRB, the ED and/or D/ADs will determine that the quality of their reviews and system of regulatory compliance is appropriate for Columbia’s HRPP, and that the reviewing IRB complies with applicable federal and state statutes in their reviews and operating procedures. These determinations may be made through various means, including review of operating procedures, attendance at IRB meetings, discussions with IRB administrators, assessment of whether federal regulatory agencies have restricted or suspended the IRB’s operations, CTSA status, and consideration of accreditation status. When Columbia relies on an external IRB, processes are in place to ensure that Columbia requirements are satisfied prior to commencement of the research. The administrative review by HRPO staff includes these considerations although individual agreements may also require additional levels of review, e.g., by a member of the IRB or by a team comprised of an HRPO staff member and an IRB member. CUIMC and NYP, collectively, have multiple-project IAAs with numerous institutions, including NYSPI, Weill Medical College of Cornell University, the National Cancer Institute (NCI) Central IRB (CIRBs; both adult and pediatric) and CU-MS, to rely on their IRBs’ reviews for certain types of research projects. Agreements with Weill Cornell Medical College and NYSPI also include their reliance on reviews conducted by CUIMC. The CU HRPO leadership (ED and DO) meets on an ad-hoc basis with representatives from external IRBs to consider issues relevant to the review of human subjects research at Columbia, unless all local issues are the responsibility of Columbia, per the respective agreement. Columbia may also enter into agreements pursuant to which Columbia relies on another institution’s IRB review for a single project. Except for research reviewed by the NYSPI IRB, Columbia IRB approval is required before implementation of any research involving human subjects, including review of records, tissues, or other derived materials. Depending upon the terms of the reliance agreement, the review at Columbia may be purely administrative (e.g., verification that PI eligibility criteria are met, that training requirements are satisfied, or that 40 Section II: Institutional Review Boards Page II - 16 IRB SOP V5.2 – February 12, 2019 approval by the PRMC, IBC, or JRSC has been issues), or may require facilitative review by an IRB member. b. Reliance on a Non-Columbia IRB for a multicenter study, consortium, or study program Columbia and (as applicable) NYP may enter into agreements through which the reviews of multiple projects are delegated to the IRB(s) of another institution that is serving as the central IRB for multiple institutions. For each such case, details of the review processes and responsibilities of each institution will be described within the agreement. Examples include the NeuroNext Consortium for which the Partners IRB is the IRB of Record, and certain studies for which the Fred Hutchinson Cancer Center IRB is the IRB of Record. Note that the terms Single IRB, Central IRB and Reviewing IRB all refer to an IRB that has been designated to review a study or group of studies for more than one study site, and may appropriately be used interchangeably in many situations. Unless otherwise directed by the ED in writing (other than the NYSPI, NCI, NCI- Pediatric, or the Weill Cornell IRB), the following procedures will be followed for every Columbia protocol that will be reviewed by a central IRB. The protocol must be submitted in Rascal and the submission must specify the designated IRB of record (reviewing IRB). The Columbia IRB will review the submission to ensure compliance with all institutional policies related to the protection of human subjects (e.g., conflict of interest, radiation safety, institutional biosafety committee, etc.). The processes that the HRPO will follow to ensure appropriate review for each protocol are provided in Section VI. The HRPO may develop additional procedures/processes that will be applied to specific studies or research programs that rely on IRB review by a non-Columbia IRB. The IRB will establish a QA process for internal protocols reviewed by these processes, including but not limited to the IRB’s existing not-for-cause audit program. c. Columbia Serving as IRB of Record for Non-Columbia Entities The situations in which Columbia may serve as the IRB of Record for a non- Columbia institution vary widely, ranging from coverage of collaborating investigators who will only perform analysis of identifiable specimens or data, to serving as the central IRB for multiple projects at multiple institutions. In situations whereby Columbia researchers collaborate with researchers from other institutions, Columbia may act as IRB of record for the collaboration for certain low risk research. The ED or DO will review each such situation and make a determination that such reliance on the Columbia IRB is appropriate. 41 Section II: Institutional Review Boards Page II - 17 IRB SOP V5.2 – February 12, 2019 Decisions to enter into agreements that are broad in scope, and/or involve research that presents greater than minimal risk of harm to subjects, require consultation with relevant IOs, the VPRO, the EVPR, and/or OGC. All IAAs must be signed by the appropriate IO. Coverage by Columbia and/or NYP of collaborating individuals who will be engaged in non-exempt research but are not affiliated with an institution that has an IRB must be formalized through execution of an Individual Investigator Agreement (IIA). Through the terms of the IIA, the collaborator agrees to abide by specific ethical principles while engaged in the Columbia-directed research. 2. Research Conducted at CU by Investigators Affiliated with Other Institutions Columbia University officials and faculty are often approached by investigators at other institutions for cooperation in their research, e.g., through assistance with recruitment, or to perform specific tests or analyses. In addition, investigators at other institutions may propose a study to be conducted, all or in part, at Columbia. The need for review by the CU IRB will depend upon the nature of the involvement of the individual who is affiliated with CU in the former situation, and the proposed use of CU facilities, resources, and/or non-public data in the latter circumstance. All clinical research conducted at CUIMC must be covered by a Columbia IRB protocol with a Columbia PI. Therefore, the protocol and supporting documents for the proposed research should be submitted to the ED or DIM for administrative review and a determination as to whether formal CU IRB review (i.e., review by a CU IRB in accordance with these SOPs) is also needed. Supporting documents include: a) the informed consent document(s) or justification for waiver of consent; b) study instruments if applicable; and c) a copy of the IRB approval from the external IRB. CU IRB review is not generally required if, in the case of proposed collaboration, the individual who is affiliated with CU is not engaged in human subjects research, i.e., the individual will not: a) intervene or interact with living individuals for research purposes; b) obtain individually identifiable private information for research purposes; or c) receive a direct federal award. For example, department Chairs or Deans may be asked to assist in the distribution of surveys to faculty or students. Because these individuals would not be considered to be engaged in the research, IRB approval is not required for University offices or officials to inform members of the University about research or provide them with information about contacting investigators if they wish to participate. A detailed explanation of when an institution is engaged in research can be found in the OHRP October 16, 2008, “Engagement of Institutions in Research,” which provides the basis for the Columbia engagement philosophy. However, even though “formal” CU IRB review may not be required because Columbia is not engaged in the research, the administrative review by the ED or DIM will be conducted to ensure that the research has been appropriately reviewed by an external IRB for the protection of subjects at Columbia or NYP. 42 Section III: Preparation of Submissions Page III - 2 IRB SOP V5.1 – April 12, 2018 instances, HRPO staff will contact a member of the study team to explain that the document has been revised, and advise the study team that they should immediately advise the IRB if the changes are not acceptable. The researcher has access to all parts of the Rascal file for each of his/her protocols except the internal IRB notes and documents, the identity of the reviewer(s), Meeting History (i.e., minutes of convened meetings), and correspondence transmitted between HRPO staff and/or between IRB members and HRPO staff. The submission is locked against changes by the research team at any time that it has been submitted and is in an IRB queue. IRB review is based on the material submitted electronically by the researchers via Rascal. Literature reviews by members and notes entered by staff or IRB members to document conversations with members of the research team may also be considered during the review. Annual financial conflict of interest statements and evidence of satisfactory completion of Columbia-developed training courses in the Rascal Training Center are documented electronically in accordance with Rascal procedures and reflected on the Data Sheet of the submission. Completion of required training modules via the online Collaborative IRB Training Initiative (CITI) program is documented in Rascal and appears on the Data Sheet, when appropriately accessed via the Rascal system. Designated HRPO staff have the ability to manually upload training results if automated upload from CITI to Rascal does not occur. Training requirements are described in detail in Section X.D. An electronic protocol-specific conflict of interest statement is also required for the PI, all co-investigators, study coordinators, regulatory coordinators and any other engaged personnel as part of the submission approval process. B. IRB Abbreviated Submission Process The IRB supports an abbreviated submission process for studies that have a stand-alone protocol. The process requires completion of all Rascal fields that provide information regarding local implementation of the study, for multicenter studies, or information that is not covered in the stand-alone protocol. However, entering study information into the relevant Rascal fields is not required, as the Columbia IRBs will rely on the attached stand- alone (e.g., sponsor's) protocol for review of the overall objectives. The abbreviated process eliminates the need to summarize the complete protocol on various pages in Rascal. If a researcher selects the Abbreviated Submission checkbox in Rascal, and a section is not covered by the submitted stand-alone protocol, the researcher must go back and provide this information on the appropriate page(s) in Rascal. C. Personnel The Rascal Personnel page solicits information about the individuals who will be involved in with the conduct of the study. It is important that accurate information about each 45 Section III: Preparation of Submissions Page III - 3 IRB SOP V5.1 – April 12, 2018 individual’s role is entered, because of related eligibility and training requirements. Non- Columbia collaborators should generally not be listed in the Personnel section. 1. Principal Investigators a. Eligibility A Columbia Officer of Instruction, with a full-time appointment at the rank of instructor or higher, may serve as a Principal Investigator (PI) on a protocol. Full- time Officers of Research at the rank of Research Scientist (or equivalent) or higher may also serve as a PI. Exceptions will be considered by the appropriate authority on the relevant campus (Reference Document #13). Criteria for serving in the role of PI are determined by Columbia and articulated in the Faculty Handbook, Principal Investigator section. For research that will be conducted at NYP by an employee of NYP who is not also affiliated with Columbia, clearance from NYP Administration is required in lieu of satisfaction of the criteria articulated in the Faculty Handbook. IRB staff facilitate the review by NYP Administration. Rascal will permit only one individual to be named as PI. CUIMC requires that oncology studies managed through the Clinical Protocol & Data Management Office name an individual (Investigator) who will provide clinical coverage for when the PI is traveling or otherwise unavailable. The role of the Investigator who will ensure this coverage should be explained in the respective Role & Experience field of the Personnel section in Rascal. The IRB may determine that for other, e.g., higher risk studies, the study team also designate a covering Investigator for similar reasons. A student may not serve as the PI on a protocol. Appropriately qualified students may have a substantial role in a research project, but supervision by a faculty advisor is required. In most cases, the faculty advisor also serves as the PI for the project. When this is not the case, another qualified individual must be identified to serve in this role. b. Research and Human Subject Determinations No research involving human subjects may be conducted without IRB approval or determination of exempt status, the latter in accordance with 45 CFR 46, and by designated HRPO staff or IRB Chairs. Exempt research is human subjects research that falls into designated categories that are exempt from the requirements of the federal regulations. Although a PI may make a determination of “Not Human Subjects Research” (i.e., the regulatory definitions of “research” and/or “human subject” are not met) on his/her own without submission to the IRB, the PI will be responsible for any noncompliance that results, if that decision is later found to be incorrect. Consultation with IRB staff or submission of the protocol to the IRB via 46 Section III: Preparation of Submissions Page III - 4 IRB SOP V5.1 – April 12, 2018 Rascal is recommended whenever it is not clear if the regulatory definitions of “research” and “human subject” are met. 2. Roles and Responsibilities Responsibility for the ethical conduct of all study procedures conducted under the auspices of Columbia University, from initial recruitment efforts, through completion of data analysis and closure, rests with the PI, who may delegate tasks but retains responsibility for them. IRB correspondence that provides the outcome of IRB reviews or decisions, e.g., approval letters and notifications of suspensions, whether sent through the Rascal correspondence queue or in hard copy, is addressed to the PI. Rascal correspondence requesting clarification or changes to submitted Events is sent to the PI as well as to those members of the research team designated per Rascal procedures (Reference Document #95). Personnel who are named on a protocol must be assigned a role. Careful consideration should be given to role assignment as some carry specific responsibilities, have additional requirements for training, or require signoff by the individual before the protocol can be submitted. If an individual is listed in one role (e.g., as an individual who is Non- Engaged Personnel), and duties for the study change such that he/she will be performing duties beyond that role (e.g., moving from Non-Engaged Personnel to Other Engaged- Personnel, Coordinator, etc.), a modification should be submitted to revise his/her role. Research personnel who will be affiliated with Columbia on a temporary basis and are engaged in human subjects research conducted by Columbia investigators must generally be appointed as an Officer of Research or Instruction and are constrained by the parameters for the position as described in the Columbia University Faculty Handbook. Individuals who will be observing research procedures for 3 months or less, usually for training purposes, must adhere to the requirements of the University’s Guidelines for Short-Term Visitors in Research-Related and Clinical Activities (Document #306). 3. Training Before a protocol will be approved by a CU IRB, the PI must complete required training as described in Section X.D. Study personnel must complete applicable training prior to participation in the research.  Most required training modules must be accessed via the Rascal Training Center; for these courses, evidence of completion is maintained electronically within Rascal.  Security Essentials training that is required annually for the CUIMC workforce and anyone named on a CUIMC protocol is managed outside of the Rascal system. HRPO staff do not monitor completion, but access to Rascal and certain other electronic systems will be restricted if this training is not completed within the specified timeframe. This training, while not targeted specifically to research 47 Section III: Preparation of Submissions Page III - 7 IRB SOP V5.1 – April 12, 2018 2. Submission Materials: Modification Any proposed change or modification to a protocol that was approved by the IRB must first receive prospective IRB approval, unless such a change is necessary to eliminate or minimize an imminent harm to subjects. If the protocol was eligible for expedited review, and the proposed change(s) are such that the protocol remains eligible for expedited review, the modification may also be reviewed under an expedited review process. If the overall protocol requires review by the convened IRB, and the change is non- substantive in nature, the IRB may approve such a change by expedited review. Full Board review of the modification is required if the proposed change(s) are substantive in nature (e.g., increase risk, add a treatment arm, expand the study population to include vulnerable subjects, etc.). If it is discovered during the course of a study that there is the potential for imminent harm to subjects, and changes must be made to eliminate or mitigate the risks, but there is no time to obtain IRB approval, the investigator should implement any change(s) necessary and subsequently submit a modification to the IRB so that such change(s) are documented and approved by the IRB for all subsequent research activities under the protocol. This modification must be submitted to the IRB at the earliest possible opportunity after the change is made. Submission of an Unanticipated Problem report in Rascal may also be necessary if the criteria, as described in Section III.D.4., are met. Any change in the protocol that is necessary for the enrollment of a specific subject (e.g., deviation from the approved inclusion/exclusion criteria) or to address a temporary situation (e.g., a temporary drug shortage) also needs prospective IRB approval. If a subject who does not meet the enrollment criteria is enrolled, even if the sponsor has agreed to such enrollment, this would be considered a protocol deviation (if the study team identified and submitted the change for IRB review, and IRB approval was issued, before enrollment) or violation (if the study team did not [both] identify the change and obtain IRB approval for it, before enrollment) by the IRB. Protocol deviations and major violations that occur during the study should also be submitted as modifications, unless the violation involves an unanticipated problem involving risks to subjects; the latter should be submitted using the unanticipated problem event module. Minor violations may be submitted at the time of renewal. See Section III.D.6 for additional information regarding submission of reports of deviations and violations. The Modification Information page (Reference Document #69) must be completed in Rascal when changes to the approved protocol are requested. This form solicits the following information: a. summary of and explanation for the requested modification or addendum to the approved protocol; 50 Section III: Preparation of Submissions Page III - 8 IRB SOP V5.1 – April 12, 2018 b. if the submission includes a protocol violation, and if so, how many of each are included; c. checklist to designate the pages that are being revised as part of the modification submission; d. designation of the modification as an administrative change, if applicable; e. study enrollment status (e.g., enrollment ongoing, study closed to enrollment) and a summary of information needed to explain the study status; and f. if the consent form has been revised as a result of the protocol change. The following information or documentation must be attached or included: a. clean and highlighted copies of revised documents, or a clean copy with a clear explanation of what has changed, if documents have been revised; b. supporting documentation of modification from the sponsor, if applicable; c. updated Personnel page in Rascal, if personnel change is involved; d. updated Subjects page in Rascal to reflect the current number of enrolled subjects; e. updated pages in Rascal as appropriate, e.g. if a change in recruitment is suggested, revision to the Recruitment and Consent page is required to reflect the change; f. updated Procedures page in Rascal to reflect procedure change (e.g. biological specimens, imaging); and g. plans to obtain updated consent from enrolled subjects if new information that may affect their willingness to continue participation is involved, or justification for not obtaining updated consent when new information is available. 3. Submission Materials: Renewal (Continuing Review) Notification that continuing review is required will be sent automatically by the Rascal system to investigators at 90, 60, and 30 days prior to the expiration date of the current IRB approval. In addition, Rascal will send notification of an “expired” status on the day that the IRB approval expires, if a renewal has not yet been submitted and approved, and will send reminders every 30 days until a current IRB approval status has been obtained. Investigators are required to submit renewal requests in Rascal and are strongly encouraged to submit appropriate reports for ongoing research activities no fewer than 60 days prior to the expiration date of the IRB approval for the study. Expiration date reminders are a sent as a courtesy to researchers. It is the responsibility of the study team to ensure that renewals are submitted in time to allow for appropriate review by the IRB prior to expiration. Researchers relying on an external (non-CU) IRB must comply with the specific timeframe for that IRB. 51 Section III: Preparation of Submissions Page III - 9 IRB SOP V5.1 – April 12, 2018 The Renewal Information Page (Reference Document #61) must be completed in Rascal. This form solicits the following information: a. study enrollment status, (e.g., enrollment ongoing, study closed to enrollment) and summary of information needed to explain the study status; b. list of relevant literature, interim findings, and publications; c. report of subjects who were enrolled utilizing the Short Form consent process; d. inquiry regarding recent Data Safety and Monitoring Committee (DSMC) or Board (DSMB) or other relevant multi-center trial reports, if applicable; e. request for recent Progress Report, if applicable and available; f. if the renewal includes a modification, a summary of the proposed change(s), checklist to designate the pages that are being revised as part of the included modification and if the consent form has been revised as a result of the protocol change; and g. if the submission includes a protocol violation, and if so, how many are included. In addition to completing the Renewal Information page, the Subjects page in Rascal must be updated to reflect, at a minimum: a. original number of participants anticipated; b. number of participants enrolled/accrued to date at CU site; c. number of participants enrolled/accrued last year at CU site; d. number of participants who completed the study at CU site; e. number of participants expected to enroll/accrue next year; f. number of participants who remain on study and number who are off study; g. number of, and explanation for participant complaints at CU site; h. number of, and explanation for participants removed by the PI; i. number of, and explanation for participants who withdrew from the study; j. number of participants who died while on study; k. demographic information for subjects enrolled at CU site; l. subject population justification; m. subject compensation and justification, if applicable; n. consent waiver or alteration requests, if applicable; and o. recruitment URL, if applicable. The following information or documentation must be attached: 52 Section III: Preparation of Submissions Page III - 12 IRB SOP V5.1 – April 12, 2018 a. changes or amendments since the most recent approval (including changes in personnel since the most recent approval and additional information about risk associated with the study); b. why the study is being closed, including documentation to support premature closure, when applicable and if available; c. if any research-related activities were conducted after the date of expiration, if the study is expired; d. confirmation that all requests and/or requirements as requested by the IRB have been addressed; e. number of participants enrolled to date at CU site; f. number of participants enrolled last year at CU site; g. number of participants expected to enroll next year; h. number of participants who remain on study i. number of participants who completed the study at CU site; j. number of participants expected to enroll next year; k. number of, and explanation for participant complaints at CU site; l. number of, and explanation for participants removed by physician; m. number of, and explanation for, participants who withdrew from the study; n. number of, and explanation for participants removed by the PI; o. number of, and explanation for participants lost to follow-up; p. number of, and explanation for participants who have died while on study; q. number of, and explanation for participant complaints at CU site; r. number of participants enrolled to date at other sites; and s. demographic information for subjects enrolled at CU site. 6. Submission Materials: Report of Protocol Deviation or Violation All deviations from and violations of Columbia policies or IRB determinations, including the requirement for adherence to the approved protocol, must be reported to the IRB. A protocol deviation is defined as a divergence from the approved protocol, IRB determinations or IRB policies for one subject or to address a temporary situation that is identified by the research team and approved by the IRB before implementation. A protocol violation is defined as a divergence from the approved protocol, IRB determinations or IRB policies that was implemented without prospective approval by the IRB and was not implemented to avoid or minimize imminent harm. Protocol violations may be considered as non-compliance with the federal regulations for the protection of human subjects. Information on submission materials required for Deviations or 55 Section III: Preparation of Submissions Page III - 13 IRB SOP V5.1 – April 12, 2018 Violations when Columbia University is the Reviewing IRB and when a non-Columbia IRB is the Reviewing IRB is detailed in Columbia University IRB Guidance for Protocol Deviations and Violations (Reference Document #364). The IRB recognizes that some deviations (e.g., inclusion/exclusion criteria) are identified shortly before the subject is scheduled for randomization or entry into the study and that a quick review by the IRB is important for the study. For funded studies, the sponsor’s concurrence that the individual may be enrolled should be provided with the submission. In time-sensitive situations, the investigator should follow his/her submission to the IRB with an e-mail outside of Rascal to the Manager of the IRB that approved the study. If a Protocol Violation is unexpected, at least possibly related to the research, and involves risks to subjects or others, it is considered an UP and must be reported to the IRB within one week (5 business days) using the UP functionality in Rascal. The description of the circumstances surrounding the deviation/modification should be clearly stated in the Unanticipated Problem Report (Reference Document #188). If the UP results in a modification to the protocol, consent form or other study related documents, those changes should be submitted as a Modification. Protocol violations related to medication dose errors should also be discussed with the subject, in accordance with the underlying philosophy of NYPs Disclosure Policy (Policy #E145). Protocol Violations that are not UPs are categorized as Minor or Major Violations. Major Violations are those that violate the rights or welfare of subjects, negatively affect the integrity of the study or result in the need for a change to the protocol or consent document(s). In most cases, they will be reported to the IRB as a Modification and should be clearly stated in the summary section of the Modification Information form (Reference Document #69). However, when reporting of the major violation coincides with submission of a Renewal, the violation may be reported within the Renewal application (Reference Document #61). Modification submissions to report Major Violations should include the PI’s assessment that the event does not meet the UP criteria and must be reported to the IRB promptly, generally within one week (5 business days) of occurrence or, if it is not known to the PI at that time, of discovery by the PI, to provide an opportunity for the IRB to assess, within a reasonable timeframe relative to protection of subjects, whether the study should continue, and whether changes to study procedures are required. Minor violations are violations that are not UPs and do not meet the criteria to be considered major violations. These should be reported to the IRB at the time of continuing review, in a list or log that includes all UPs, deviations, and violations. The log should reflect when individual submissions of each UP, deviation, or major violation were made. The following information should be included for deviations and violations: a. a complete description of the deviation/violation; b. an explanation of why the deviation is necessary, or why the violation occurred; 56 Section III: Preparation of Submissions Page III - 14 IRB SOP V5.1 – April 12, 2018 c. whether the deviation affects, or the violation affected, the risk/benefit ratio for subjects, integrity of the research data, and subjects’ willingness to continue study participation; and d. for protocol violations, a description of the corrective measures that will be taken to prevent a recurrence of the same or similar violations. Supporting documentation may be attached electronically, and should be provided whenever available or pertinent. 7. Submission Materials: Expanded Access, Including Emergency Use Expanded access, including emergency use, is the use outside of a clinical trial of an investigational medical product (i.e., a drug/biologic or device that has not been approved by FDA). Information related to submission materials for each category of expanded access are discussed below: a. Emergency Use FDA regulations permit use of an investigational drug or device, without IRB approval, in very limited circumstances. Such use is considered to be an emergency clinical use, and FDA requirements for the research use of an investigational agent do not apply. The FDA must be notified of all emergency use situations by the manufacturer or sponsor. When possible, the HRPO should be notified in advance of the proposed emergency use. For some emergency use situations, notification to the HRPO may be necessary because the manufacturer of the product may not agree to ship the product until a letter confirming the IRB is aware of the impending use of the investigational product is received. The CTO (IAP) should also be notified when emergency use of an investigational product occurs. Only emergency life-threatening situations that will be treated with an investigational agent, for which an approved protocol is not available, in an effort to save a patient’s life or loss of a part of the body (e.g., eye, limb, etc.) are to be considered for the emergency use exemption. None of these situations will be considered research and therefore data collection for research purposes is not permitted. Physicians are encouraged to contact the IRB office immediately if such a situation arises. Consent options for emergency use situations are defined below; proposed procedures must be described in the emergency use request to the IRB prior to the emergency use: 1) if the consent form is prepared at the time of submission of the emergency use request, it should be attached and submitted with the Emergency Use (EU) notification; 57 Section III: Preparation of Submissions Page III - 17 IRB SOP V5.1 – April 12, 2018  Note that Subpart D of 21 CFR 312 (Responsibility of Sponsors and Investigators) is applicable to expanded access use of investigational drugs/biologics. c. IRB Submission Process for Non-Emergency Expanded Access Use of Investigational Drugs or Biologics Prior IRB review and approval is required for all non-emergency expanded access use. Emergency use procedures are discussed separately in this document. For individual-patient expanded access, submit the following: 1) documentation confirming criteria under 21 CFR 312.305(a) noted above are met; 2) investigator’s determination that the probable risk to the person from the investigational drug is not greater than the probable risk from the disease or condition; 3) confirmation of IND submission to the FDA or FDA-issued IND if available; 4) confirmation that informed consent will be obtained via an acceptable consent process; 5) for individual-patient expanded access INDs only, notification that the investigator has requested a waiver under 21 CFR 56.105 of the requirements noted in 21 CFR 56.108(c) requiring full committee review as indicated on FDA Form 3926; and 6) documentation evidencing FDA determination that the patient cannot obtain the drug under another IND or protocol, e.g. FDA approval for Single-Patient expanded access to proceed. If a waiver under 21 CFR 56.105 is selected on FDA Form 3926, concurrence by the IRB Chairperson or another IRB member can serve as prospective IRB review. For intermediate-size patient populations (IND or Protocol), submit the following: 1) documentation confirming criteria under 21 CFR 312.305(a) are met; 2) statement of whether the drug is being developed or is not being developed and description of the patient population to be treated. If the drug is not being actively developed, an explanation why the drug cannot currently be developed for the expanded access use and under what circumstances the drug could be developed; 3) if the drug is being studied in a clinical trial, clarify why patients to be treated cannot be enrolled in the clinical trial and under what circumstances the sponsor would conduct a clinical trial in these patients; 4) confirmation of IND submission to the FDA or FDA-issued IND if available; and 60 Section III: Preparation of Submissions Page III - 18 IRB SOP V5.1 – April 12, 2018 5) confirmation that informed consent will be obtained via an acceptable consent process. Convened IRB review is required for intermediate-size patient populations (IND or Protocol), as per 21 CFR 56.108(c). For treatment IND or treatment protocol, submit the following: 1) documentation confirming criteria under 21 CFR 312.305(a) are met; 2) confirmation of IND/Protocol submission to the FDA or FDA-issued IND if available; and 3) confirmation that informed consent will be obtained via an acceptable consent process. Convened IRB review is required for treatment INDs or treatment protocols, as per 21 CFR 56.108(c). Important Notes on timing of Expanded Access Use:  A non-emergency expanded access IND (individual-patient, intermediate or treatment) goes into effect 30 days after the FDA receives the IND, or after an earlier notification is provided by the FDA that the expanded access use may begin.  There is no 30-day waiting period for expanded access use of a drug or biologic under an individual patient protocol or intermediate-sized patient population protocol, however the protocol must be submitted to the FDA and receive IRB approval before treatment may begin.  There is a 30-day waiting period from the date the FDA receives a treatment protocol, before expanded access use of a drug or biologic under a Treatment protocol may begin, unless the FDA notifies the sponsor that treatment may begin earlier. d. Non-Emergency Expanded Access (Devices) An unapproved medical device may normally only be used on human subjects through an approved clinical study in which the subjects meet certain criteria and the device is used in accordance with the approved protocol by a clinical investigator participating in the clinical trial. However, there may be circumstances under which a physician may wish to use an unapproved device to save the life of a patient or to help a patient suffering from a serious disease or condition for which no other alternative therapy exists. If enrollment in an existing clinical trial protocol is not possible (e.g., a patient is not eligible for any ongoing clinical trials, or there are no ongoing clinical trials to address 61 Section III: Preparation of Submissions Page III - 19 IRB SOP V5.1 – April 12, 2018 the patient’s condition), patients/physicians may request expanded access to investigational devices under one of three alternative mechanisms:  Emergency Use  Individual-Patient/Small Group (commonly referred to as “Compassionate Use”)  Treatment Use IRB Submission Process for Non-Emergency Expanded Access Use of Investigational (i.e., non-FDA approved) Medical Devices FDA approval is required for all non-emergency expanded access use. Emergency use procedures are discussed separately in this document. For Individual-patient/small group (“compassionate use”): Ensure the following criteria are met: 1) the patient has a life-threatening or serious disease or condition; and 2) no generally acceptable alternative treatment for the condition exists. If an IDE exists or there is no IDE for the device, submit the following: 1) confirmation that the IDE sponsor (can be device manufacturer or a physician who has submitted the IDE to conduct the clinical study for the device) has submitted an IDE supplement requesting approval for a compassionate use under section 21CFR812.35(a), which includes: a) a description of the patient's condition and the circumstances necessitating treatment; b) a discussion of why alternatives therapies are unsatisfactory and why the probable risk of using the investigational device is no greater than the probable risk from the disease or condition; c) an identification of any deviations in the approved clinical protocol (if any) that may be needed in order to treat the patient, and; d) the patient protection measures that will be followed which includes: i. obtaining informed consent from the patient or a legal representative; ii. an independent assessment from an uninvolved physician; iii. clearance from the institution as specified by their policies*; iv. concurrence of the IRB chairperson*; and v. authorization from the IDE sponsor, if an approved IDE exists for the device. 2) Confirmation of IDE submission to the FDA or FDA-issued IDE if available; 62 Section III: Preparation of Submissions Page III - 22 IRB SOP V5.1 – April 12, 2018 established within the CTO to provide education, training and support to S-Is with respect to FDA regulations to S-Is, and help ensure appropriate documentation and trial monitoring to satisfy regulatory requirements. S-Is are encouraged to consult with CTO early in the development of their protocol. The CTMAP provides support with respect to monitoring S-I research. When any study is conducted by an S-I, the submission for IRB review must include a Form of Notice by CU Faculty IND/IDE Holder letter (Reference Document #367) that documents that the Department Chair and the S-I both have provided commitment that adequate resources will be provided that will permit the conduct of the study in compliance with FDA regulatory requirements. In addition, the submission for IRB approval must include a plan for monitoring of the study in accordance with 21 CFR 312. 2. Submission Materials: Research with Biologics Protocols that involve research with biologics require similar submission materials and are reviewed similarly to research with investigational drugs. A biologic is defined as any virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or analogous product, or arsphenamine or its derivatives, applicable to the prevention, treatment or care of diseases or injuries of man. Review and approval by the IBC is required for biologics that involve recombinant deoxyribonucleic acid (DNA). When gene transfer is involved, documentation of a decision by the NIH Recombinant Advisory Council (RAC), when their review is required, is expected. In addition to the material listed in the Section III.D relating to the type of Event, the following material and/or information is required for all research involving biologics: a. sponsor protocol, if industry-sponsored; b. IDB, if industry-sponsored; c. package insert, if approved drugs are administered; d. documentation of current FDA status, if an IND for a biologic (BB-IND) is indicated; e. completion of the Drugs/Biologics page to list the investigational product4 (Reference Document #92) for each agent involved; and f. data and safety monitoring plan. 4 The FDA considers an investigational product to be one that is the focus of a clinical investigation. Accordingly, if a drug, device, or biologic that is already approved by the FDA is the focus of the protocol being submitted, it should be described on the Drugs/Biologics page. 65 Section III: Preparation of Submissions Page III - 23 IRB SOP V5.1 – April 12, 2018 If the study constitutes S-I research, additional consideration must be given as to how compliance with FDA requirements will be maintained, as described in Section III.E.1 above. Documentation from the PI and department chair as described in Section III.E.1 must also be provided. 3. Submission Materials: Device Research Research that involves a medical device may vary in design, from investigation of the safety, efficacy and practicality of investigational devices, to comparison of two approved devices, to the evaluation of approved devices for indications other than those for which they were approved. A medical device is defined in the current federal Food, Drug and Cosmetic Act 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: a. recognized in the official National Formulary, or the United States Pharmacopoeia, or any supplement to them; b. 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 c. 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. In addition to the material listed in the preceding Section III.D relating to the type of Event, the following material and/or information is required for all research involving devices: a. device manual, if industry-sponsored; b. documentation of current FDA status, (e.g., FDA approval letter with terms if an IDE is indicated, printout of approved indications from FDA website if 510(k) approval, etc.); c. completion of the Device Page to list the investigational product5 (Reference Document #92) for each device involved; d. data and safety monitoring plan; e. device management plan; f. Clinical Investigator Agreement; and 5 The FDA considers an investigational product to be one that is the focus of a clinical investigation. Accordingly, if a drug, device, or biologic that is already approved by the FDA is the focus of the protocol being submitted, it should be described on the respective page. 66 Section III: Preparation of Submissions Page III - 24 IRB SOP V5.1 – April 12, 2018 g. Confirmation of Medicare contractor, National Government Services (NGS) or Centers for Medicare and Medicaid Services (CMS) coverage decision, if the study meets the requirements for device studies that must be submitted for a determination of NGS billing clearance. 1) If the IDE study was approved before 1/1/2015: the study must be submitted to the Medicare contractor, National Government Services (NGS); the PI of the study submits request to the Medicare Administrative Contractor provider/local NGS representative and receives a determination letter. 2) If the IDE study was approved on or after 1/1/2015: the Sponsor must submit request for coverage to CMS. Approval will be posted on the CMS website and all sites must be listed on the www.clinicaltrials.gov record for the study. If the study constitutes S-I research, additional consideration must be given as to how compliance with FDA requirements will be maintained, as described in Section III.E.1 above. Documentation from the PI and department chair as described in Section III.E.1 must also be provided. A sponsor’s determination of non-significant or significant risk, and basis for the determination, is recommended for studies that do not already have an approved IDE. If this information is not provided, the IRB will make its determination absent this input; if additional information is needed, the determination, and hence the overall review, may be delayed. Ultimately, after review of all material and justification provided by the sponsor and investigator, the IRB’s determination is final. When devices that are not yet FDA-approved will be used, plans for handling of the investigational article should be included in the submission to the IRB. IDE regulations at 21 CFR 812.110 require that the investigator manage the device supply such that they are used only with subjects under the investigator's supervision. In addition, the investigator may not supply an investigational device to any person not authorized to receive it. Upon completion or termination of the clinical investigation or the investigator's part of the investigation, or at the sponsor's request, the investigator must return to the sponsor any remaining supply of the device or otherwise dispose of the device as the sponsor directs. Device use must be tracked and records retained of each device and its disposition; this is particularly important for implantable devices. When devices are labeled with a serial number, the number must be recorded within or connected to the research records of the individual who received the device. The following factors should be addressed: a. When recruitment and ordering of devices will begin (i.e., that no patients will be contacted or recruited, and no investigational devices will be ordered, until IRB approval has been obtained and applicable contracts have been signed); b. That the PI is responsible for ordering, and proper accountability, handling, and storage, of devices, as follows; 67 Section III: Preparation of Submissions Page III - 27 IRB SOP V5.1 – April 12, 2018 c. for those subjects who are not able to provide informed consent, a description of efforts to identify an appropriate surrogate, family notification of research participation, when possible, and plans for informing the patient of participation if/when the patient regains cognitive capacity; d. plans for identifying and contacting family members after participation if such contact could not be done prior to participation; e. procedures for determining who is a legally authorized representative (LAR), when permission will be sought from someone other than the parent of a minor child; f. description of the efforts by which the community has been advised of the planned emergency research. The Surrogate Consent section of the IRB Informed Consent Policy provides detailed information about options for surrogate consent. At the time of continuing review, unless required sooner by the IRB, the investigator will need to summarize efforts made to contact family members of those subjects who were not able to provide their own consent. Planned Emergency Research must be distinguished from emergency use of an investigational FDA-regulated product for an individual patient. The former is considered research but the latter is considered clinical care. Both may involve waiver of informed consent through the provisions of 21 CFR 50.24 (i.e., Exception from Informed Consent Requirements for Emergency Research). 5. Submission Materials: Research involving Pregnant Women, Fetuses, and Neonates In addition to the material listed in the preceding Section III.D related to the type of Event, the following material is required for all research involving pregnant women, fetuses, and neonates: a. information to support the findings required by Subpart B of 45 CFR 46 for participation of pregnant women and fetuses in research (See Reference Document #357 for additional detail); and b. a description of the additional precautions that will be taken to ensure that legally effective informed consent is obtained, when women in labor will be enrolled. Institutional guidance (Reference Document #103) on when it may be acceptable to approach women in labor for purposes of research participation should be considered when developing this information. 6. Submission Materials: Research Involving Prisoners 70 Section III: Preparation of Submissions Page III - 28 IRB SOP V5.1 – April 12, 2018 In addition to the material listed in the preceding Section III.D relating to the type of event, the following material is required for all research involving prisoners: a. information to support the findings required by Subpart C of 45 CFR 46 for participation of prisoners in research; b. a rationale for including prisoners in the research, or limiting research participation to prisoners; and c. approval or letter(s) of support from applicable departments or facilities, if already obtained. (See Reference Document #356, and search for “prisoner” within the document, for additional information that may be relevant if the research is subject to the requirements of federal agencies other than DHHS or FDA). 7. Submission Materials: Research Involving Children In addition to the material listed in the preceding Section III.D relating to the type of Event, the following material is required for all research involving children, i.e., information to support the findings required by Subpart D of 45 CFR 46: a. a description of procedures used to obtain assent, or justification for not obtaining assent; b. when assent will be obtained, identification of the ages for which assent will be required, and a description of the method used to document that assent was provided, e.g., written documentation on an assent form, verbal agreement documented by researcher in the research record; c. description of procedures for obtaining, and forms used to document, parental permission; d. the investigator’s initial assessment of risk level and potential for benefit to subjects or others; e. sufficient information for the IRB to determine the level of risk, and whether there is the prospect of direct benefit to the individual subject; f. a statement regarding the inclusion of wards if the research involves greater than minimal risk without the possibility of direct benefit, i.e., whether wards will be included and if so, what procedures have been developed for identifying an advocate for each ward; and g. procedures for determining who is a legally authorized representative, when permission will be sought from someone other than the parent of a minor. The Child Involvement page in Rascal, which solicits the information described above, must be completed by the investigator if he/she has indicated that children will be involved in the study. This section is designed to remind the investigator of information required, depending upon the level of risk and prospect of benefit to subjects. 71 Section III: Preparation of Submissions Page III - 29 IRB SOP V5.1 – April 12, 2018 Researchers who anticipate that children will be included among their study subjects are advised to review the Columbia policy, Research Involving Children (Reference Document #107), which articulates the institution’s expectations for parental permission, assent, risk/benefit analysis, and related issues. The policy is posted on the CU HRPO website. (See Reference Document #356, and search for “children” within the document, for additional information that may be relevant if the research is subject to the requirements of federal agencies other than DHHS or FDA). 8. Submission Materials: Research Involving Other Vulnerable Adults In addition to the material listed in the preceding Section III.D relating to the type of Event, the following material is required for all research involving vulnerable populations: a. a description of procedures incorporated into the protocol to ensure that the rights and welfare of individuals with decreased autonomy will be protected; b. a description of procedures that will be utilized to obtain legally effective consent; c. where applicable, a description of procedures that will be utilized to determine competency to provide consent initially or during the course of participation, the latter for studies in which it is expected that cognitive capacity may become diminished; d. procedures for determining who is a legally authorized representative or appropriate Health Care Proxy (HCP), when one is needed to provide consent; e. description of procedures that will be utilized to minimize risks related to the vulnerability of the prospective subjects; and f. description of procedures that will be in place to eliminate elements of undue influence or coercion. Additional details on obtaining Surrogate Consent can be found in the CU Informed Consent Policy. 9. Submission Materials: Research Involving Non-English Speaking Individuals If the inclusion of non-English speaking individuals is anticipated, the consent document(s) must be translated by an acceptable translator, as defined in the CU IRB Enrollment of Non-English Speaking Subjects in Research Policy (Reference Document #101), into the prospective subjects’ first language or language of choice. Certification of the translation, as described in the Policy, must be provided. It is not sufficient in most cases to rely on verbal translation of English consent documents during the consent process. 72 Section III: Preparation of Submissions Page III - 32 IRB SOP V5.1 – April 12, 2018 committee during its review, if available, and approval letter from the local committee, should be considered in the CU IRB review. If CU IRB review occurs before the local ethics committee review, CU approval to commence study procedures would be contingent upon receipt of the approval by the local ethics committee, which should employ standards that are appropriate for Columbia’s HRPP. Investigators conducting research in foreign countries must be aware of and abide by all applicable Columbia polices related to international activities. The Office of Research Compliance and Training website provides additional information on International Research. In addition to the material listed in the preceding Section III.D related to the type of Event, the following material or considerations are required prior to approval by the IRB: a. documentation of knowledge of local context, i.e., details of the local context to provide a basis for the IRB review; b. local IRB/ethics committee approval, evaluation by a consultant, or input from an individual or entity with adequate knowledge of the study site should be submitted with the application (if this documentation is available at the time of the CU IRB submission), obtained by the IRB during the renewal process, or in the case of local approval, provided after approval (if the local review board requires CU approval first); c. agreement that consent documents will be translated after the English version is approved, if the study population is expected to include non-English speaking individuals; d. identification of local individuals, if any, who will participate in conducting the research, and a description of their roles; and e. where appropriate, letter(s) authorizing conduct of the study at the international institution or organization. Researchers conducting international research are advised to review the OHRP International Compilation of Human Research Standards for information about local regulations and laws in international sites. The RCT must be advised of any research proposed to be conducted in a sanctioned country. All research conducted within such countries must abide by the restrictions outlined by the U.S. Department of the Treasury. 12. Submission Materials: Substudies 75 Section III: Preparation of Submissions Page III - 33 IRB SOP V5.1 – April 12, 2018 Substudies may be defined as projects that are developed to answer a research question that has arisen as a result of an ongoing study, i.e., there is a logical evolution or expansion of the initial research hypothesis, or auxiliary studies are offered to participants in a study, e.g., optional pharmacokinetics or genetic procedures. Rascal includes questions to capture whether the study includes one or more components that apply to a subset of the overall study population, as well as the target enrollment for each substudy. The determination of whether a substudy should be submitted as a separate, new Rascal submission, or as a modification to an approved protocol, is dependent on the relationship of the new procedures to the existing protocol, e.g., objectives, subject population, consent procedures, study instruments, risk and benefit. In general, if the population, consent procedures, and objectives vary significantly from the approved study, such that the IRB can no longer make one set of required determinations for the entire Rascal protocol, the substudy should be submitted separately. In such cases, the approved main study should be referenced in the new submission so that, where feasible, both can be reviewed by the same IRB and primary reviewers. In addition to the material listed in the preceding Section III.D relating to the type of Event, the following material is required for all substudies: a. an explanation of the relationship between a previously approved, or recently submitted, protocol and the substudy that is being submitted for review; b. a description of the modifications, if any, that will be made and submitted to the IRB for review, to recruit from the main study, if applicable; c. if subjects from the main study will be recruited for the substudy, a description of how the substudy will be introduced to the subjects; and d. consent procedures for the substudy, and additional consent forms, if applicable; e. details of data use and sharing, if applicable, between studies. 13. Submission Materials: Collaborative Research that will not be Conducted under an IRB Authorization Agreement Researchers affiliated with Columbia may collaborate with individuals from other institutions on a specific research project involving human subjects. When this occurs, the IRB needs to know enough about the activities at each site to be able to accurately determine the risks and benefits of the activities for which CU has oversight, and the documentation, if any, required from each site. In addition to the material listed in the preceding Section III.D relating to the type of Event, the following material/information is required for all collaborative research: a. for all collaborative projects: 76 Section III: Preparation of Submissions Page III - 34 IRB SOP V5.1 – April 12, 2018 1) the name and title of, and contact information for, the individual (identified by role) who is responsible for the conduct of the project at the collaborative site(s); 2) the procedures that will be conducted at each site (level of detail will be dependent upon CU role, e.g., whether CU is the lead institution, one of the study sites, coordinating center, etc.); 3) the funding mechanisms involved, if any; 4) identification of the individual who will serve as the overall PI for the project; 5) a clear description of what CU personnel will be doing as well as what will be done, in relation to the research study, at CU; 6) proposed use of consent forms, i.e., whether CU forms or the other institution’s forms will be used, and for which site(s) each consent form will be used, if each institution has one or more; and 7) appropriate authorization for research at the site, and IRB approval, as applicable; 8) appropriate agreement for the transfer of data or material. 1) 2) 3) 4) 5) 6) 7) b. In addition, if CU is the lead institution: 1) the status of IRB approval at each site or arrangements previously made or in progress to delegate authority for review; 2) description of services provided by coordinating centers, and identification of the coordinating centers, if applicable; 3) a written plan explaining how regulatory compliance will be ensured for each site engaged in the research. The plan should include: a) details on how local IRB approval will be obtained and maintained at each site; b) a description of procedures in place to ensure that the informed consent document approved by the local IRB does not have substantive changes in the purpose, procedures, and risks sections from the form approved by the CU IRB; c) a plan for ensuring that UPs involving risks to subjects or others will be reported to the local and CU IRBs; 77 Section III: Preparation of Submissions Page III - 37 IRB SOP V5.1 – April 12, 2018 In addition to the material listed in the preceding Section III.D relating to the type of Event, the following material/information is required: a. contact information for each site; b. documentation that each site has granted permission for the research to be conducted at the facility; and c. IRB/ethics approval, if the site is engaged: 1) whether each site has an IRB and if so, whether it has approved the research; or 2) plans to enter into, or attachment of an executed, IAA whereby the site relies on the Columbia IRB. Additional guidance: a. If the external sites are international, please refer to Section III.E.11 of these procedures for additional guidance. b. If there will be collaboration with investigators from other institutions, please refer to Section III.E.13and/or III.E.14 of these procedures for relevant guidance. c. If the external sites are in the U.S., but not local, please refer to Section III.E.11. of these procedures for guidance on obtaining adequate knowledge of the local context. 17. Submission Materials: Transfer of Research when PI is Leaving Columbia If the PI of a study that is approved by the IRB will be leaving Columbia, plans for closure of the study or continuation with another PI at Columbia must be considered. A submission to the IRB is required, the nature of which, e.g., modification, renewal or closure, will be determined by the decisions that are made about the future status of the study at Columbia. Common situations and options for IRB submissions are described below. IRB staff should be consulted about appropriate action for other circumstances. For active research: a. if the study(ies) will be transferred to another institution, an intervention is involved, and subjects will be offered the opportunity to continue participation at the new institution, a modification that describes plans for notifying subjects, determining whether they will continue participation, and safely transferring or ending subject participation should be submitted to the IRB; b. if the study(ies) will be transferred to another institution, subjects are not currently enrolled or all subjects have completed study procedures or have withdrawn, but identifiable data will be transferred, a modification should be 80 Section III: Preparation of Submissions Page III - 38 IRB SOP V5.1 – April 12, 2018 submitted to describe how confidentiality of data will be maintained in accordance with the terms to which the subjects agreed; c. if the study(ies) will not be transferred to another institution, a qualified individual must be identified to serve as PI, and a modification submitted to implement the change; and d. an appropriate agreement must be executed prior to any data or material that was originally collected at Columbia is transferred to an external site. For research that has not yet started or for which all activities have concluded, but the study remains open while awaiting publication, a closure submission should be submitted to the IRB. 18. Submission Materials: Federally-Supported or Conducted Research Per the requirements of 45 CFR 46.103(f), the IRB must review the entire grant application for research that is funded by a federal agency. A complete copy of each application, from face page to the end, excluding appendices, should be attached to the IRB submission. Where necessary to safeguard confidentiality, salaries and similar information may be redacted. This material will be reviewed by the IRB to (at a minimum) ensure that all funded procedures are included in the research protocol, evaluate relationships among collaborators to determine necessary approvals, and confirm key personnel. During its review of research that is supported or conducted by specific federal agencies, and/or is subject to the requirements of those agencies, or is subject to specific federal policies, the IRB will consider the requirements of the respective agencies and policies as they relate to the protection of human subjects, and make specific determinations regarding them (e.g., related to informed consent, reporting, monitoring, etc.). These requirements are in addition to the requirements for approval of research that the IRB considers for all research involving human subjects. Awareness by researchers of these regulations, policies, and affiliated required determinations will facilitate inclusion, in the submission to the IRB, of the information that must be considered before these determinations can be made. Reference Document #356, Additional Requirements for Protocols Funded by Specific Federal Agencies or Subject to Specific Federal Policies, provides guidance to facilitate a complete submission that addresses the additional regulatory concerns of these agencies and policies. Particular attention should be paid when preparing protocols that are subject to Department of Defense regulations. Requirements vary depending upon the DoD component. Detailed guidance is provided in Reference Document #356, Additional Requirements for Protocols Funded by Specific Federal Agencies or Subject to Specific Federal Policies. 81 Section IV: Processing of Submissions Page IV - 1 IRB SOP V5.1 – April 12, 2018 IV. Processing of Submissions to the IRB: Pre- and Post-IRB or ARC Review A. Preliminary Review of Submitted Events Upon submission, a preliminary review (“pre-review”) by experienced HRPO staff is conducted. This section provides an overview of the pre-review process. Complete details of the process, including the criteria on which the review is based, will be found in the Review section (Section VI) of these procedures; details will vary based on the type of Event. The outcome of the pre-review is that the submission is either logged in to the Chair’s queue or returned to the researcher. If the submission is returned, it will have another staff review upon resubmission. Details of the routing process can be found in Reference Document #24. New protocols undergo a cursory review upon submission to preliminarily assess the appropriate level of review so they may appropriately be routed for pre-review. Upon completion of each pre-review of new protocols submitted for the first time, the staff reviewer completes a reviewer form (Reference Document #34a, “Reviewer Form: New Protocols [Biomedical]” or #34b, “Reviewer Form: New Protocols [Behavioral]”) and enters comments in the Notes field for the Event. The protocol will be assigned to an IRB based upon the level of review required and, where applicable, the type of research: CUIMC IRBs 1-3 for full board non-oncology and non- genomic studies; CUIMC IRB 4 for full board oncology studies; CUIMC IRB 5 for full board genetic/genomic and oncology studies; CUIMC IRB Exp for protocols eligible for expedited review; the CUIMC ARC for determination of exemption for Not Human Subjects Research (NHSR), i.e., definition of research is not met, or NHSR per 45 CFR 46, i.e., research, but the definition of human subject is not met; or MS IRB for protocols originating from CU-MS researchers. A reviewer form is also completed by staff during pre-review of renewal (continuing review) submissions (Reference Document #110, “Renewal Pre-review Form”), and the review of closure reports is guided by specific criteria (Reference Document #111, “Closure Return Criteria”), followed by a summary entry in the Notes field. A template for notes for modification submissions is used to guide, in a consistent manner, the administrative review of modifications to approved protocols. The outcome of staff pre-review of other Events such as review of unanticipated problems is also entered in the Notes field. At the conclusion of the pre-review for new protocols, renewals, modifications, closures, and unanticipated problem reports, the reviewer facilitates the Event being logged in (i.e., accepted for review) or returned to the researcher for revision or additional documentation/information. Correspondence in Rascal to the study team follows each return. As previously indicated, if the submission is returned, the action will undergo another staff review upon resubmission. The format for the commentary that is entered in the Notes section can be found in Reference Document #20. B. Routing of Submissions to IRB per Level of Review Required Submissions are routed to the Chair’s queue after being logged in by HRPO staff. Individuals designated as Chair or Vice Chair (either, for purposes of these review sections, a “Chair”) review pre-review comments entered in the Notes field relevant to each Event to obtain a synopsis of the Event, facilitate awareness of regulatory considerations, and view the level of review recommended by the staff reviewer. Depending upon the level of review required, the Chair will review the Event him/herself or distribute it to an experienced IRB or Committee 82 Section IV: Processing of Submissions Page IV - 4 IRB SOP V5.1 – April 12, 2018 45 CFR 46.101(b)(1) if the questions are directly related to evaluations of standard educational practices in accepted educational settings. Research involving prisoners is not eligible for exemption. In addition, except for exemption (6), which is reflected in the FDA regulations as 21 CFR 56.104(d), the exemptions at 45 CFR 46.101(b) do not apply to research that involves an investigational drug, device, or biologic, (i.e., activities that are subject to FDA regulations). As noted in the CU IRB Informed Consent Policy (Reference Document #10), in the spirit of the principles of the Belmont Report in which autonomy of the individual and the voluntariness of participating in research are fundamental ethical principles, the IRB strongly recommends that informed consent be obtained for certain exempt studies. For exempt studies that allow for direct interaction between the investigator and human subjects, participants should minimally be informed of the following: that the activity is research, the procedures that are involved in the study, the nature of the risks (e.g., little, if any expected inconvenience or harm), that participation is voluntary and that they may withdraw from the study at any time. Exempt approvals are communicated to the research team via electronic Letter of Approval (LOA) (Reference Document #93) by HRPO staff. Exempt determinations are valid for a period of five years. At the end of the five-year period, a renewal application must be submitted for tracking purposes. Unless the research has changed in such a manner that the project is no longer exempt, approval will be provided for an additional five year period (Reference Document #9). A list of exempt determinations by the ARC is generated via the Rascal IRB minutes function to document the reviews, and the resultant document is approved by HRPO staff. Copies of approved minutes, including the ARC minutes, are forwarded to the IOs. Although not required from a regulatory perspective, such notification affords the IOs the opportunity to be aware of, and if warranted, provide input about all human subjects research that may be conducted under the auspices of the institution. The FDA allows four exemptions from IRB review of activities that are FDA-regulated: a. any investigation which commenced before July 27, 1981 if specific conditions are met (21 CFR 56.104(a)); b. any investigation which commenced before July 27, 1981 and IRB review was not required (21 CFR 56.104(b)); c. emergency use of an investigational article (21 CFR 56.104(c)); and d. taste and food quality evaluations and consumer acceptance studies if specific conditions are met (21 CFR 56.104(d)). 3. Level of Review: Expedited The IRB may utilize an expedited review procedure as authorized by 45 CFR 46.110 and 21 CFR 56.110. 85 Section IV: Processing of Submissions Page IV - 5 IRB SOP V5.1 – April 12, 2018 As stated above, at CUIMC, new protocols for which the recommended level of review per the pre-review is “expedited” are assigned to CUIMC IRB Exp. The CU-MS IRB Chair or designated reviewer conducts expedited reviews of protocols originating from CU-MS researchers except in cases where the protocol is assigned for review by a CUIMC IRB, either because certain expertise is required that is not available on the CU-MS IRB, or the proposed research is FDA-regulated. Upon review of a submission, if the criteria for expedited review appear to be met, a Chair will designate the protocol as eligible for expedited review by selecting the appropriate expedited review category(ies) in Rascal, if the researcher did not select the category(ies). The Chair may also revise, add or remove category selections. The Chair will then distribute the protocol for review by selecting a primary reviewer and sending the protocol electronically to the reviewer’s queue. The reviewer has access, electronically within Rascal, to all information and documents that were submitted by the study team. A qualified member of the Board (in general, one who has one year or more of IRB experience) or the Chair may serve as the primary reviewer. If necessary to ensure the necessary reviewer expertise, additional reviewers may be selected. In accordance with federal regulations, the designated reviewer(s) may act for the Board to approve or require changes to an Event under review, and must ensure that all review criteria are met. To facilitate this process, reviewers are routinely provided with tools and information to guide their review, including a primary reviewer form, decision charts, and educational information, as part of the CU IRB educational initiatives. In reviewing the research, the reviewer may exercise all of the authority of the Board except disapproval. If the reviewer finds that the protocol does not meet the criteria for expedited review, he/she will refer it for review by the convened IRB. The IRB may utilize the expedited review process for the following types of research (45 CFR 46.110; 21 CFR 56.110): a. minor changes in research previously approved by the convened IRB or through an expedited review process during the period for which approval is authorized; a guidance document (Reference Document #112) has been drafted to assist in determining whether a change is minor; in addition, minor modifications are addressed in Section VI.C.2. of these SOPs; b. research activities involving no more than minimal risk for which the only involvement of human subjects will be in one or more of the categories identified on the list as published by the FDA and DHHS. As with the review of exemptions described in the preceding Section, if there is any information that needs to be verified with the investigator, the designated reviewer or staff may initiate this contact and should document it in Rascal. The reviewer who is conducting the expedited review may enter comments in the Notes section of Rascal and make hard copy documents such as handwritten or typed comments available to the HRPO staff as documentation of the review and to assist in preparation of correspondence. These documents will not be considered part of the official file unless they are attached to the protocol in Rascal. 86 Section IV: Processing of Submissions Page IV - 6 IRB SOP V5.1 – April 12, 2018 A list of research that has been approved under an expedited procedure, including PI and title, is provided to the members of IRB Exp as soon as practical after such expedited approval, via IRB minutes. Members who participated in the expedited review will respond to questions, if raised, from the members concerning the Events approved in this manner. The Board will not use the expedited procedure if its use has been suspended or terminated by the FDA, OHRP or the University. Approvals made by expedited review are communicated to the research team by electronic LOA (Reference Document #93). 4. Level of Review: Facilitative/Administrative/118 Three functional categories exist in Rascal in the expedited review option list: Facilitative Review, Administrative Review of certain types of awards to support multiple projects involving numerous investigators, and review per 45 CFR 46.118. The first was developed to allow processing of protocols subject to IAAs when CU is not the IRB of Record (additional detail in following section), the second was implemented to permit processing of submissions for sponsored projects for which human research exists only in the individual studies that involve research with human subjects, and each receive their own IRB approval, and the third was instituted to facilitate processing of protocols for which procedures involving human subjects were not defined at the time of IRB submission or personnel need to be hired and trained before human subject involvement commences but IRB approval is required by the funding agency. a. Facilitative review A facilitative review is conducted when the IRB has agreed to rely on the review of an IRB from a non-Columbia institution, via an executed IAA or other reliance agreement. The specific review process is contingent upon the relevant Agreement. The Boards may act in liaison with the IRBs of other institutions as necessary to assist in the review of joint and cooperative projects involving multiple sites and/or investigators. The ED or DO may agree to permit another IRB with whom an IAA has been executed to act as the IRB of Record for studies to be conducted by, or with the assistance of Columbia personnel, at the facilities of another institution. In addition, a CU IRB may agree to function as the IRB of Record for another investigator and/or institution if the project involves material collaboration with Columbia personnel. Details of the level of, and criteria for, review of protocols that are subject to an IAA can be found in Section VI. A. Approvals under these categories are reported to members of the IRB that conducted the facilitative review and to IOs via approved minutes. b. Administrative review This Columbia-specific expedited review category is utilized for submissions that describe a funding mechanism for human subjects research, but do not, in and of themselves, describe specific research projects. Examples are center grants and training grants. Each project that will involve human subjects and be supported by the award will be submitted individually within Rascal if conducted by Columbia personnel; for other projects, the PI of the award must maintain documentation of 87 Section IV: Processing of Submissions Page IV - 9 IRB SOP V5.1 – April 12, 2018 with new protocols, the Chair selects a primary reviewer who has the appropriate expertise to review the submission. The Chair may distribute the renewal electronically to a consultant who has Rascal access but the consultant would generally be considered to be a secondary reviewer. Information that is available electronically, and should be reviewed by a primary reviewer, is provided by the most appropriate means (e.g., in hard copy or electronically) to any consultant who would not normally have access in Rascal. An attempt is made to assign the protocol to the Board member who reviewed the initial submission or the most recent renewal request. The reviewer has access to the complete historical file (i.e., where applicable, the paper file that was in existence before the conversion to Rascal) for the study as well as all renewal information during his or her review and may request that specific information be provided to all Board members prior to the convened IRB meeting A prisoner representative is assigned to review each renewal that involves prisoners as subjects. The reviewer is guided by the Prisoner Research review form (Reference Document #94). 3. Primary Reviewer System: Modifications, Unanticipated Problem Reports The Chair selects a primary reviewer (him/herself, another regular member of the IRB, or an alternate member) to review the submission. As with new protocols, the Chair selects a primary reviewer who has the appropriate expertise to review the submission. The Chair may distribute the modification electronically to a consultant who has Rascal access but the consultant would generally be considered to be a secondary reviewer. An attempt is made to assign the Event to a Board member who reviewed the initial submission or the most recent renewal request. Consultants may also be used when the requisite expertise to assess the information provided cannot be provided by available Board members. Information that is available electronically, and should be reviewed by a primary reviewer, is provided by the most appropriate means to any consultant who would not normally have access in Rascal. All Board members have electronic access via Rascal to the complete modification or Unanticipated Problem Report submission: the Report of the Unanticipated Problem or modification summary, protocol Data Sheet, Study Description, current consent documents, Notes field affiliated with the event (which includes pre-reviewer notes), and supporting documentation attached by the researcher or HRPO staff. Board members also have access to the complete historical file (i.e., prior submissions and IRB actions) for the study for their review. The Board determines, based in part on the primary reviewer’s recommendation, whether the report is complete or additional information is required. In addition, a determination is made as to whether the protocol and/or consent document(s) should be revised, if this is necessary as a result of the UP or modification and has not already been initiated by the study team. When revision to the consent form(s) and/or protocol is deemed necessary, the Board determines whether currently enrolled subjects also need to be informed, how this should be documented and, in the case of revised consent forms, whether their consent should be re- obtained. Finally, the Board may impose restrictions on the research (e.g., more frequent 90 Section IV: Processing of Submissions Page IV - 10 IRB SOP V5.1 – April 12, 2018 reporting, suspension of enrollment, suspension of the study, termination, etc.) if review of an unanticipated problem report or modification results in a determination that the risk/benefit ratio has become less favorable. Details of all review processes are in Section VI, IRB Review of Human Subjects Research, of these procedures. 4. Primary Reviewer System: Closures The IRB Chair selects a primary reviewer (him/herself, another regular member of the IRB, or an alternate member) to receive the electronic submission. An attempt is made to assign the event to a Board member who reviewed previous submissions for the protocol. The Rascal system requires that all closure requests be assigned to a Board meeting regardless of the level of review that the study had previously received. Board members have access to the complete historical file (i.e., prior submissions and IRB actions) for the study during their review. Closure reports are voted upon as a group when presented at a convened meeting. Any Board member may request discussion of an individual closure report. Requests for closures of protocols that are assigned to IRB Exp are listed on an agenda after which members of IRB Exp are notified that these items are available for their review until a specific date. If an IRB member has a concern about any closure request, the appropriate action, which may include obtaining additional information or recommendation to the study team that the protocol remain open, is taken. When all issues are resolved, the agenda listing the closures is converted into minutes and approved by the Exp Chair on rotation. A similar process is followed for closure requests for exempt protocols that are assigned to the Administrative Review Committee, with staff members conducting the reviews. D. Post-Review Procedures Minutes will be generated to reflect actions taken by the Board during convened meetings. The minutes of IRB meetings will document separate deliberations, actions, and votes for each event undergoing review by the convened IRB, as well as a summary of any Board discussions of controverted issues. Notification to the IRB members of actions taken by the Chair or designated reviewers in- between meetings occurs via inclusion in the agenda and minutes of subsequent meetings. Details of the process by which minutes are generated can be found in the Minutes Section (VII.E.) of these procedures. E. Notification to Researcher: General Process Outcomes of all reviews will be communicated to researchers as expeditiously as possible after the review is complete (See Reference Document #95 for an explanation of the members of the research team to whom correspondence is sent within Rascal). Minutes of full Board meetings, which include the outcome of an event reviewed at the meeting, will usually be approved in their entirety prior to transmittal to researchers of the outcome of individual events via Rascal. In cases where the protocol is not approved as submitted, specific requests and concerns of the reviewer and/or Board, as appropriate to the level of review, will be communicated to the study team via Rascal. Wherever possible, guidance as to an acceptable response and the basis for the requests or concerns will be included. Minutes for the entire meeting need not be approved before correspondence requesting revision(s) or an electronic LOA (Reference Document #93) documenting approval for an 91 Section IV: Processing of Submissions Page IV - 11 IRB SOP V5.1 – April 12, 2018 individual Event is sent, provided the minutes for that Event are approved (through documented contact with the Chair outside of Rascal or via use of the Immediate Action feature in Rascal). Each Board will follow DHHS and FDA regulations for reporting its findings and actions to the investigator, and when applicable, to the institution (45 CFR 46.108; 46.103(b)(4); 46.103(b)(5); 21 CFR 56.108 (a)(1)). Electronic copies of minutes are provided to IOs with a cover memo highlighting items that may require additional institutional consideration or to note compliance or other matters of concern that were discussions by the Board. 1. Notification: Approval and Outcome of Review All requests and concerns of the IRB, whether from full Board or expedited review, or evaluation to determine whether exemption is appropriate, must be addressed satisfactorily by the research team before a protocol may be approved or receive an exemption determination. Approval of a human subjects research activity, whether exempt or non-exempt, will be documented and communicated by means of an electronic LOA that will be posted in Rascal. The LOA will reflect the approval provided electronically by the Chair/designee through approval of minutes or of previously pending items, or by an authorized expedited reviewer, and must be signed by a designee with signing authority. The LOA used for initial and continuing approval of a protocol will contain information about the study and its approval status. This document includes: a. title of the research project; b. name of PI; c. for funded projects, funding award number and protocol version number, if available; d. level of IRB review and outcome; e. approval and expiration dates; f. consent and HIPAA requirements (if any); g. study status; h. conditions to the approval, e.g., requirement to translate consent documents; i. information regarding Researcher Responsibilities including continuing review requirements, reporting of UPs, the need to submit modifications for approval prior to implementation, and request to submit a closure report once the study has been completed; and j. electronic signature of the individual with signing authority. The LOA for changes to an approved research project, or for a continuing review request that includes changes to the research project, will include, in addition to the items noted above, a description of the modification. When a CU IRB serves as the IRB of Record for a non-Columbia institution, the Columbia research team is responsible for providing a copy of the LOA to each institution, as appropriate. 2. Notification: Disapproval 92 Section V: IRB Pre-review and Review Criteria Page V - 1 IRB SOP V5.1– April 12, 2018 V. IRB Pre-review and Review Criteria This section describes how the IRB determines whether an Event that has been submitted should be approved. Each variable (e.g., type of Event, type of research) is described individually as guidance for use in the review process. Investigators should be familiar with the criteria for review for their particular type of research and Event submitted, to facilitate the inclusion of all necessary information in the submission. The IRB will consider all applicable factors for a given submission. For example, if a submission is for a new protocol that involves an investigational drug administered to children, the information described in each of the relevant sections (i.e., background, drugs/biologics, and subjects pages) will be evaluated. The IRB will conduct a review of non-exempt research in accordance with 45 CFR 46, New York (NY) state law, and institutional policies, and ensure that all elements of 45 CFR 46.111 are met prior to approval of the new protocol or other Event. When the research involves FDA regulated drugs, devices or biologics, the IRB will also consider the applicable parts of Title 21 of the Code of Federal Regulations [21 CFR 50, 56, 312, 600, 812]. Review of all research involving human subjects, including exempt research, must ensure that all new personnel have completed the appropriate web-based human subjects training course, TC0087, Human Subjects Protection (HSP), that is available through the Rascal Training Center. Individuals must complete both the HSP and research-related HIPAA (TC0019) courses if they are affiliated with the CUIMC campus or are conducting research that involves the creation, use, or disclosure of Protected Health Information (PHI). Additional training requirements for specific types of research are detailed in Section X.D. Specific details regarding review of each type of Event are in the Event-specific sections of these procedures (Section VI.A). Protocols that meet the criteria for exemption and those for which the definition of research or human subject are not met, will initially be pre-reviewed by HRPO staff, then reviewed by the IRB Chair at CU-MS, or by a member of the Administrative Review Committee at CUIMC. Chairs of the CUIMC IRBs also have the authority to make exemption or “Not Human Subjects Research” determinations, i.e., that the definition of research or human subject is not met. Research involving procedures that fall within one or more of the allowable categories for expedited review will initially be pre-reviewed by HRPO staff, and then reviewed by the IRB Chair, or an experienced Board member designated by the IRB Chair. In accordance with federal regulations, the designated reviewer(s) may act for the Board to approve or require changes to a study under review. Board action is required, however, for a decision to disapprove any study. Protocols that constitute research with human subjects and do not meet the criteria for exemption or expedited review will initially be pre-reviewed by HRPO staff, and then reviewed at a convened meeting of the IRB. This process is described more fully in Sections VI and VII. 95 Section V: IRB Pre-review and Review Criteria Page V - 2 IRB SOP V5.1– April 12, 2018 At each step of the review process, the Event under review is assigned a specific status (e.g., submitted, logged in, distributed, approved, pending, returned, deferred) to reflect the action of the researcher, staff, or Board, as applicable. See Reference Document #04, Actions of the IRB, for specific terms and the description of each. “IRB review” in these SOPs, unless specified otherwise, refers to: a) review by the convened Board when full Board review is warranted; and b) review by an experienced IRB member when submissions undergo an expedited review. Similarly, in reference to review processes, “IRB” means the convened IRB for full Board reviews and an experienced IRB member for expedited reviews. “Panel” refers to an IRB (also referred to as a “Board”) or the ARC (labeled “Admin” in Rascal). A. Pre-review of Submitted Events Upon submission of an Event in Rascal, a pre-review by HRPO staff is conducted. Depending upon the nature of the Event, the process may differ but will result in all cases in a decision to accept the submission for review (i.e., “log in” the submission), or return it to the PI to obtain missing information, clarification of information, and/or missing documentation. An overview of the process was provided in Section IV.A. Details of the process for each type of Event are described below. During the pre-review, HRPO staff will attempt to obtain missing information, clarification of information, or missing documentation through contact with the study team before returning the submission in accordance with the return criteria described in the following sections. When it is determined to be most efficient or necessary, however, the submission will be returned. Reasons for return include, but are not limited to: information must be entered in Rascal fields to enable the IRB to meet criteria for approval or for tracking or reporting purposes, requests are numerous and a return would be more productive, and/or contact with the study team outside of Rascal has not been successful or effective. 1. Pre-review: New Protocols New protocols are pre-reviewed for completeness and compliance with applicable policies and statutes. The staff reviewer determines whether the protocol is complete and should be logged in or returned, enters comments about the protocol in the Notes section of Rascal for consideration by the Board reviewer, completes a reviewer form, attaches the reviewer form to the protocol in Rascal as an internal document, and recommends a level of review based on federal regulations and institutional policy. At this stage, protocols will be returned for the following reasons: a. the PI is not qualified, PI is not in the CU Directory, or the PI’s privileges have been suspended by the IRB; b. the PI has not completed the required human subjects/S-I/FDA/HIPAA/Minors/ Good Clinical Practice (GCP) training specific to the proposed study procedures; 96 Section V: IRB Pre-review and Review Criteria Page V - 3 IRB SOP V5.1– April 12, 2018 c. the Attributes section of the submission does not appropriately identify the IRB of Record and all Relying Institutions, as applicable; d. the study is cancer-related research but the procedures page indicates “no” to cancer-related research or, if it indicates “yes”, an appropriate selection (e.g. “Involves an intervention designed to diagnose, treat, prevent, or provide supportive care to subjects with or at risk of developing a form of cancer; Uses specimens or patient information to assess cancer risk, clinical outcomes or response to therapies, Utilizes observation or surveillance [no intervention or alteration of patient status],” etc.) has not been designated; e. the sponsor’s protocol, investigator’s brochure, device manual or other component of the formal description of the research is missing and efforts to obtain document(s) outside of Rascal have not been successful; f. the grant application or other documentation of funded procedures is not included, if the study is externally funded and efforts to obtain document(s) outside of Rascal have not been successful; g. consent/parental permission/assent documents are not included, a waiver of consent may be appropriate, and a waiver of informed consent/parental permission/assent is not requested; h. consent/parental permission/assent documents are not included, a waiver of consent would not be appropriate, and efforts to obtain document(s) outside of Rascal have not been successful; i. consent/parental permission/assent documents do not include all of the required elements of consent/assent; j. study instruments (e.g., surveys, questionnaires, interview or focus group guides, etc.), if a specific number of instruments, or a specific instrument, are referred to but multiple instruments are not provided; k. plans for recruitment are not provided; l. there is no data and safety monitoring plan, if the study is greater than minimal risk; m. the study will enroll children but the subjects page (vulnerable subjects section) does not reflect this population; n. the study involves the use of an investigational product but the Drugs/Biologics or Devices page(s), as applicable, has not been completed; o. Appendix A (for recombinant DNA, including gene transfer), B (for infectious agents), D (for lasers), H (for certain research procedures involving ionizing radiation exposure) or I (for controlled substances) is required but is not attached; p. the study involves administration of unapproved radiopharmaceuticals intended to solely obtain information about the human physiology, pathophysiology, biochemistry or metabolism of the drug but there is no confirmation of RDRC review or final outcome; 97