Central IRBs in Multicenter Studies. Adrian Hernandez, MD July 17, 2015

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1 Central IRBs in Multicenter Studies Adrian Hernandez, MD July 17, 2015

2 CTTI USE OF CIRBS RECOMMENDATIONS FIRST US INDEPENDENT IRB FDA REGULATIONS NCI CIRB FORMED AAHRPP FOUNDED VA CIRB NCI CIRB: 881 ENROLLED INSTITUTIONS/AFFILIATES NIH DRAFT POLICY: SINGLE IRBS MULTISITE RESEARCH OPRR(OHRP) SINGLE PROJECT ASSURANCE FDA GUIDANCE USE OF CENTRAL IRBS FDA GUIDANCE: IRBS REGISTRATION NEURONEXT AWARDED NINDS STROKE NETWORK AWARDED NATIONAL RESEARCH ACT COMMON RULE OIG RPTS: INDEPENDENT IRBS & IRBS TIME FOR CHANGE OHRP GUIDANCE: KNOWLEDGE OF LOCAL RESEARCH CONTEXT CONF ON ALTERNATIVE IRB OPTIONS (NIH, OHRP, AAMC, ASCO, VA) OIG STING: COAST IRB NEJM MENIKOFF EDITORIAL ANPRM: REVISION TO COMMON RULE SEVERAL NIH RFAS WITH CIRB NCI CIRB INDEPENDENT MODEL CTTI CENTRAL IRB ADVANCEMENT RECOMMENDATIONS

3 CTTI USE OF CIRBS RECOMMENDATIONS FIRST US INDEPENDENT IRB FDA REGULATIONS NCI CIRB FORMED AAHRPP FOUNDED VA CIRB NCI CIRB: 881 ENROLLED INSTITUTIONS/AFFILIATES NIH DRAFT POLICY: SINGLE IRBS MULTISITE RESEARCH OPRR(OHRP) SINGLE PROJECT ASSURANCE FDA GUIDANCE USE OF CENTRAL IRBS FDA GUIDANCE: IRBS REGISTRATION NEURONEXT AWARDED NINDS STROKE NETWORK AWARDED NATIONAL RESEARCH ACT COMMON RULE OIG RPTS: INDEPENDENT IRBS & IRBS TIME FOR CHANGE OHRP GUIDANCE: KNOWLEDGE OF LOCAL RESEARCH CONTEXT CONF ON ALTERNATIVE IRB OPTIONS (NIH, OHRP, AAMC, ASCO, VA) OIG STING: COAST IRB NEJM MENIKOFF EDITORIAL ANPRM: REVISION TO COMMON RULE SEVERAL NIH RFAS WITH CIRB NCI CIRB INDEPENDENT MODEL CTTI CENTRAL IRB ADVANCEMENT RECOMMENDATIONS Discussed on last week s Grand Rounds and archived here: nih.collaboratory.org

4 CTTI USE OF CIRBS RECOMMENDATIONS FIRST US INDEPENDENT IRB FDA REGULATIONS NCI CIRB FORMED AAHRPP FOUNDED VA CIRB NCI CIRB: 881 ENROLLED INSTITUTIONS/AFFILIATES NIH DRAFT POLICY: SINGLE IRBS MULTISITE RESEARCH NATIONAL RESEARCH ACT OPRR(OHRP) SINGLE PROJECT ASSURANCE COMMON RULE OIG RPTS: INDEPENDENT IRBS & IRBS TIME FOR CHANGE OHRP GUIDANCE: KNOWLEDGE OF LOCAL RESEARCH CONTEXT FDA GUIDANCE USE OF CENTRAL IRBS CONF ON ALTERNATIVE IRB OPTIONS (NIH, OHRP, AAMC, ASCO, VA) FDA GUIDANCE: IRBS REGISTRATION OIG STING: COAST IRB NEJM MENIKOFF EDITORIAL NEURONEXT AWARDED ANPRM: REVISION TO COMMON RULE NINDS STROKE NETWORK AWARDED SEVERAL NIH RFAS WITH CIRB NCI CIRB INDEPENDENT MODEL Use of central IRBs at the multi-cdrn level in PCORnet CTTI CENTRAL IRB ADVANCEMENT RECOMMENDATIONS

5 Types of Central IRB Models Shared model Regulatory review is handled by Reviewing IRB ( Lead IRB ) Local context review is handled by the Relying IRB Sharing occurs for initial and continuing, as well as study-wide amendments Local amendments are handled by each local IRB Non-shared model Reviewing IRB handles all regulatory review

6 Reliance Agreements These are institution-to-institution Can vary in: Scope 1 protocol Category of protocols (e.g. cancer, pediatrics) All research Voluntariness Must use vs. decide on a protocol-by-protocol basis

7 Updates on collaborative IRB review models IRBRely, IRBShare, and IRBChoice

8 IRBrely: National IRB Reliance Network NIH Collaboratory Grand Rounds July 17, 2015 Alan I. Green, MD Barbara E. Bierer, MD Principal Investigator Senior Reliance Advisor Nichelle Cobb, PhD Sabune Winkler, JD Co-Regulatory Lead Co-Regulatory Lead Amar Das, MD, PhD Informatics Lead

9 Multi-Site IRB Review: a National Issue Ethical-regulatory review by IRBs for multisite studies has been constrained by inefficiencies and questions about the value of redundant reviews. These delay or prevent initiation of multisite studies, and may not provide adequate protection for human subjects. Thus need for collaborative IRB review models for multisite studies. December 3, 2014: NIH issues draft policy to promote the use of single IRBs in multi-site clinical research studies.

10 Challenges Some reasons for reluctance to defer IRB review: liability administrative challenges possible confusion of responsibilities quality of review by other IRBs (trust) ensuring local requirements are addressed additional burden of changing internal processes to accommodate different methods of review

11 Major IRB Networks

12 Initial Conclusion While there are barriers to IRB reliance, current regional models are working. And, there is increasing willingness across the CTSA consortium to trust and test a national IRB model.

13 Proposed Solutions Central IRB (cirb): One IRB as IRB of record for all sites involved in multi-center protocols. cirbs generally focus on particular topic or disease (e.g., NeuroNext, NCI CIRB) Commercial IRB: Often used for industry-sponsored multicenter trials; also called independent IRBs IRB Share: A joint review model and Shared Review Process in which a Lead IRB approves a study; the Local Oversight IRB verifies agreement with the determination of the Lead IRB, and reviews local context issues. Reliance model: A single IRB of record, chosen on a study-bystudy basis, for the life of a study, involving a reviewing IRB and relying institutions

14 Goals of IRBrely Project Develop a standard IRB reliance agreement with supporting SOPs and informatics that: is not specific to a research area or region can be used for small and large-scale studies can be applied to a range of research areas can be expanded beyond CTSA sites Identify a clinical trial to test agreement, SOPs, and informatics infrastructure

15 Project Committees Executive Committee, including CTSA PIs from regional IRB consortial programs: Decision-Making Body Operations Committee to ensure project management and provide leadership to adhere to the timeframes and deliverables Regulatory Subcommittee to propose harmonized language for national IRB agreement and SOP framework to manage reliance Informatics Subcommittee to develop and build supporting informatics infrastructure Evaluation Group to assess the processes developed and infrastructure created

16 Components of IRBrely IRB Master Reliance Agreement A single IRB authorization form that all sites can use to cede review Standard Operating Procedures (SOPs) Spell out roles and responsibilities for Reviewing IRB, Relying Sites, Lead PI & Lead Study Team, Relying Study Teams, and Lead Regulatory Contacts (aka POCs) Informatics Support Website for information (IRBrely.org) Mechanism to join IRBrely In development: an end-to-end, workflow-based, platform for study teams and sites to communicate with each other about reliance

17 IRBrely Pilot CARRA Registry will be used to test components of IRBrely Duke University will serve as Reviewing IRB Laura Schanberg (Duke) & Duke Clinical Research Institute (DCRI) will serve as Lead Study Team Obtaining feedback from participating sites on agreement and SOPs for roll out beyond the pilot Testing forms and workflows developed in support of reliance to revise and enhance processes

18 Sites Considering Participation in Pilot Boston Children s Hospital Cincinnati Children s Medical Center Duke University Metro Health System (Cleveland, Ohio) Rainbow Babies and Children s Hospital (Cleveland, Ohio) University of California at San Francisco Medical Center University of Kansas Medical Center University of Wisconsin-Madison Children s Mercy Hospital (Kansas City, Missouri) Cleveland Clinic Foundation Indiana University School of Medicine Nationwide Children s Hospital (Columbus, Ohio) Tufts Medical Center (Boston) University of Iowa Hospitals and Clinics University of Texas Southwestern Medical Center (Dallas) Vanderbilt Children s Hospital

19 IRBrely: Key Roles Reviewing IRB Relying Sites Overall PI & Lead Study Team Site PI & Relying Study Teams IRBrely Regulatory Point of Contact (POC)

20 IRBrely: Reviewing IRB Oversees the study on behalf of relying sites from cradle to grave Reviews initial submission, amendments (changes of protocol), continuing review, reportable events (unanticipated problems, new information, noncompliance) Approves limited site-specific consent form language Acts as a HIPAA Privacy Board makes determinations regarding waivers and alterations of authorization Reviews any COI management plans provided to them by the relying site

21 IRBrely: Relying Sites Relying Sites = sites that agree to cede IRB review to the Reviewing IRB through the IRBrely Agreement Key responsibilities: ensuring study teams are trained ensuring their research teams comply with the conditions of IRB approval, other institutional policies, and applicable human subjects regulations (e.g., auditing & monitoring) reviewing and managing COIs

22 IRBrely: Overall PI & Lead Study Team The Overall PI designates a Lead Study Team Lead Study Team Responsibilities include: submitting materials to the Reviewing IRB for all sites, including changes of protocol, continuing reviews, and reportable events providing study materials, including the proposed consent form template, to study teams of relying sites For IRBrely pilot (CARRA Registry) Overall CARRA PI is Laura Schanberg, MD and Lead Study Team is DCRI

23 IRBrely: Site PIs & Relying Study Teams Site PI=local Principal Investigator (PI) Relying Study Team= study team whose institution has ceded IRB review to the Reviewing IRB Responsibilities include: following the policies and procedures of the Reviewing IRB (e.g., for reportable events, personnel changes) providing the Lead Study Team with information about study progress for continuing review and local events so they can be reported to the Reviewing IRB using the Reviewing IRB s consent form template (with some limited local language) obtaining authorization from their IRBrely POCs in the case of personnel changes, COI updates, and/or changes that may be affected by State law or institutional requirements

24 IRBrely: Regulatory Points of Contacts (POCs) Regulatory POCs=individuals at each site who: make determinations regarding whether to serve as the Reviewing IRB or cede IRB review authorize changes in order to confirm institutional requirements have been met serve as a resource for study teams regarding the IRBrely initiative Responsibilities include: communicating their institution s decision regarding IRB reliance providing information to the Reviewing IRB regarding institutional and State requirements affirming that local study team personnel have completed institutionally-required training

25 Upcoming Developments Implementing CARRA IRBrely pilot Finalizing IRBrely master national agreement Bringing CTSA sites and affiliates into the IRBrely network Rolling-out IRBrely informatics platform Collaborating with RDCRN, CTTI and PCORnet

26 IRBrely.org

27 IRBshare Todd Rice, MD, MSc Associate Professor VU HRPP Medical Director Vanderbilt University Medical Center

28 IRBshare

29 Brief History of IRBshare Funded by National Center for Research Resources (NCRR) ( ) *New* model envisioned because use of IRB reliance was rare due to Significant lack of trust between IRBs Institutional/IRB policies against transferring oversight (still true for some institutions) Initial Project Goals Maintain high level of protection for human subjects in multicenter trials Accelerate study start Up Create a scalable IRB reliance model (minimal funding required; open to all institutions) Create transparency between IRBs to promote shared expertise and practices

30 Shared Review Model LEAD IRB 1. Local investigator submits study to local IRB 2. Study reviewed according to risk level (expedited or full committee review) Committee Responsibility: 1. Determine whether study meets all federal regulatory guidelines for approval of research (e.g., 45 CFR )

31 Shared Review Model LEAD IRB 1. Local investigator submits study to local IRB 2. Study reviewed according to risk level (expedited or full committee review) BUSINESS AS USUAL Committee Responsibility: 1. Determine whether study meets all federal regulatory guidelines for approval of research (e.g., 45 CFR )

32 Shared Review Model LEAD IRB 1. Local investigator submits study to local IRB 2. Study reviewed according to risk level (expedited or full committee review) upload IRBshare System IRB Approved Documents Committee Responsibility: 1. Determine whether study meets all federal regulatory guidelines for approval of research (e.g., 45 CFR ) IRB application Consent form(s) (become model consent(s)) Protocol + IB/Device Manual Meeting minutes (redacted) Determination letter

33 Shared Review Model LEAD IRB 1. Local investigator submits study to local IRB 2. Study reviewed according to risk level (expedited or full committee review) LOCAL OVERSIGHT IRB 1. Local investigator submits study to local IRB (abbrev application recommended) 2. Shared Review Process: Study reviewed by local subcommittee (>1 IRB member) using IRBshare documents upload IRBshare System IRB Approved Documents download Committee Responsibility: 1. Determine whether study meets all federal regulatory guidelines for approval of research (e.g., 45 CFR ) IRB application Consent form(s) (become model consent(s)) Protocol + IB/Device Manual Meeting minutes (redacted) Determination letter Subcommittee Responsibility: 1. Verify (not re-review) Lead IRB s determination, AND 2. Review for site s own local context issues

34 Shared Review Model LEAD IRB 1. Local investigator submits study to local IRB 2. Study reviewed according to risk level (expedited or full committee review) LOCAL OVERSIGHT IRB 1. Local investigator submits study to local IRB (abbrev application recommended) 2. Shared Review Process: Study reviewed by local subcommittee (>1 IRB member) using IRBshare documents upload IRBshare System IRB Approved Documents download Committee Responsibility: 1. Determine whether study meets all federal regulatory guidelines for approval of research (e.g., 45 CFR ) IRB application Consent form(s) (become model consent(s)) Protocol + IB/Device Manual Meeting minutes (redacted) Determination letter Subcommittee Responsibility: 1. Verify (not re-review) Lead IRB s determination, AND 2. Review for site s own local context issues LOCAL IRB MAINTAINS OVERSIGHT

35 Shared Review Model: Amendments + Continuing Reviews LEAD IRB 1. Local investigator submits study to local IRB 2. Study reviewed according to risk level (expedited or full committee review) Committee Responsibility: 1. Determine whether study meets all federal regulatory guidelines for approval of research (e.g., 45 CFR )

36 Shared Review Model: Amendments + Continuing Reviews LEAD IRB 1. Local investigator submits study to local IRB 2. Study reviewed according to risk level (expedited or full committee review) BUSINESS AS USUAL Committee Responsibility: 1. Determine whether study meets all federal regulatory guidelines for approval of research (e.g., 45 CFR )

37 Shared Review Model: Amendments + Continuing Reviews LEAD IRB 1. Local investigator submits study to local IRB 2. Study reviewed according to risk level (expedited or full committee review) upload IRBshare System IRB Approved Documents Committee Responsibility: 1. Determine whether study meets all federal regulatory guidelines for approval of research (e.g., 45 CFR ) IRB application Consent form(s) (become model consent(s)) Protocol + IB/Device Manual Meeting minutes (redacted) Determination letter

38 Shared Review Model: Amendments + Continuing Reviews LEAD IRB 1. Local investigator submits study to local IRB 2. Study reviewed according to risk level (expedited or full committee review) LOCAL OVERSIGHT IRB 1. Local investigator submits study to local IRB (abbrev application recommended) 2. Shared Review Process: Study reviewed by local subcommittee (>1 IRB member) using IRBshare documents upload IRBshare System IRB Approved Documents download Committee Responsibility: 1. Determine whether study meets all federal regulatory guidelines for approval of research (e.g., 45 CFR ) IRB application Consent form(s) (become model consent(s)) Protocol + IB/Device Manual Meeting minutes (redacted) Determination letter Subcommittee Responsibility: 1. Verify (not re-review) Lead IRB s determination, AND 2. Review for site s own local context issues

39 Shared Review Model: Amendments + Continuing Reviews LEAD IRB 1. Local investigator submits study to local IRB 2. Study reviewed according to risk level (expedited or full committee review) LOCAL OVERSIGHT IRB 1. Local investigator submits study to local IRB (abbrev application recommended) 2. Shared Review Process: Study reviewed by local subcommittee (>1 IRB member) using IRBshare documents upload IRBshare System IRB Approved Documents download Committee Responsibility: 1. Determine whether study meets all federal regulatory guidelines for approval of research (e.g., 45 CFR ) IRB application Consent form(s) (become model consent(s)) Protocol + IB/Device Manual Meeting minutes (redacted) Determination letter Subcommittee Responsibility: 1. Verify (not re-review) Lead IRB s determination, AND 2. Review for site s own local context issues LOCAL IRB MAINTAINS OVERSIGHT

40 Workflow Lead IRB identified 1 st site with IRB approval, 1 st site to receive protocol/ready to submit to IRB, OR IRB of Overall PI PI at Lead IRB submits study Investigators at IRBshare sites contact IRBshare Liaison regarding submission requirements for their site Opportunity to recruit non-irbshare sites Lead IRB gets approval Approved consent form sent to all other site PIs Investigators modify approved consent to include their site s local language Local PIs submit to local IRB Subcommittee (> 1 member) uses Shared Review Process to review and approve study Local IRB sends approval letter to local PI when approved,

41 Division of Responsibilities Across Models Lead IRB/ CIRB Local/ Relying IRB IRB and/or HRPP responsibilities are split/shared across all models Subtle differences in each model can create confusion for IRBS and investigators

42 Preliminary Results and Lessons Learned IRBshare Master Agreement Finalized: October 2012 First Reliance: February 2013

43 IRBshare Network (n=58) Baystate Health* Oregon Health & Science University University of Iowa* Boston University Medical Center* Pennington Biomedical Research Center* University of Kansas* Children s National Medical Center* St. Claire Regional Medical Center University of Kentucky* Cincinnati Children s Hospital Medical Center* Seattle Children s Hospital University of Miami Columbia University* Stanford University* University of New Mexico Health Sciences Center* Duke University* Texas A&M University University of North Carolina at Chapel Hill * Louisiana State University A & M* The Rockefeller University* University of Pennsylvania* Louisiana State University HSC New Orleans* The Scripps Research Institute University of Pittsburgh* Louisiana State University HSC Shreveport* The University of Arizona* University of Southern California* Maine Medical Center* The University of Texas HSC at Houston* University of Texas HSC at San Antonio* Marshall University* The University of Utah* University of Texas Southwestern Medical Center Medical University of South Carolina* Tufts Medical Center University of Washington Mayo Clinic* Tufts University Vanderbilt University* Meharry Medical College Tulane University* Virginia Commonwealth University* Michigan State University* University of Alabama Birmingham* Wake Forest University Health Sciences* Mississippi State University* University of Arkansas for Medical Sciences* Washington University (St. Louis) * Mount Sinai Medical School* University of California, San Diego West Virginia University* New York University School of Medicine* University of California, San Francisco* Xavier University (Louisiana) North Shore LIH Health System University of Cincinnati* Northwestern University University of Illinois Chicago* *AAHRPP accredited (n=43); CTSA institution (n=39) CDRN Sites = 23 [CHOP/PedsNet (2); Pitt/PaTH (1); Oregon/ADVANCE (1); Chicago/CAPRICORN (2); Kansas/Greater Plains (5); Kaiser/PORTAL (0); LA Public Health/LA CDRN (2); Weill Cornell/NYC CDRN (4); Harvard/SCILHS (3); Mid-South (2); UCSD/pSCANNER (2)] States (n=28): Alabama Arizona Arkansas California Florida Illinois Iowa Kansas Kentucky Louisiana Maine Massachusetts Michigan Mississippi Minnesota New Mexico New York North Carolina Ohio Oregon Pennsylvania South Carolina Tennessee Texas Utah Virginia West Virginia Washington (Washington DC)

44 IRBshare Successes National Reliance Model: 58 institutions in 28 states have executed single master reliance agreement No funding required to support use Accelerating Study Start Up: Median of 14 days from submission to approval (n=28 reliances; 79% studies are greater than minimal risk) Transparency Shared Expertise Institutions unable to transfer oversight can streamline their review Shared Practices IRBs communicating and sharing documents/templates

45 Challenges (to all reliance models) IRB and PI understanding of responsibilities Coordination of use/implementation across diverse studies and institutions Competing IRB priorities Managing expectations of IRBs and PIs (IRB reliance relinquishing HRPP or PI responsibilities) Including institutions without an FWA Small community hospitals

46 IRBchoice NHLBI-funded R01 to expand IRBshare s master agreement and system to support multiple reliance models (full/ceded + shared) Goal: enable IRBs to identify the reliance model that works best for their PI and institution on a study-by-study basis Timeline: Release in Fall 2015