Reliance on the Review of Another IRB
Both OHRP and the FDA permit an IRB the option to rely on the review of another IRB. When this is the intention, the two institutions enter into an agreement referred to variously as either a Cooperative Agreement, an IRB Authorization Agreement or an IRB Reliance Agreement. These agreements are executed between a Reviewing IRB and one or more Relying Institutions and delineate the roles and responsibilities of the involved parties. The agreements can be for a single research study or for multiple studies (e.g., a Master Reliance Agreement). The NIH, study consortia and some funding agencies have increasingly encouraged the designation of central IRB to serve as the Reviewing IRB for all participating sites in multicenter research studies.
- Agreement: may be referred to as a Cooperative Agreement, IRB Authorization Agreement (IAA) or IRB Reliance Agreement. When the agreement is designed to cover all future multi-center studies involving two or more sites, this is usually referred to as a Master Reliance Agreement. For example, Penn and CHOP have a master reliance agreement in place since 2006.
- Determination Form: A determination form is often signed by two institutions who have already entered into a Master Reliance Agreement to document that the Master Reliance Agreement applies to a particular study.
- Multi-center Review: Where one IRB accepts responsibility to serve as the Reviewing IRB (Central IRB) for two or more of the institutions participating in a multi-center research study.
- Overall PI: The principal investigator with ultimate responsibility for the overall conduct, safety, regulatory oversight and data integrity for a multi-center research study.
- Participating Institution: An institution that is a signatory party to the Reliance Agreement.
- Relying Site: A hospital, clinic, doctor's office where research will take place and which will rely on an external IRB (Central IRB) which will serve as the Reviewing IRB for a multi-center study. When academic institutions are involved, this term incorporates the Relying IRB and the Relying Participating Institution
- Reviewing IRB or Central IRB: means the IRB that is responsible for the review, approval and regulatory oversight of a multi-center research study and serving more than one site. Sometimes referred to as the IRB of Record.
- Site PI: A principal investigator who is responsible for the conduct of the Research at their Participating Institution.
Reliance Agreements for Multi-center Research
CHOP is willing to serve as the Reviewing IRB for one or more Relying Sites. Conversely, CHOP is willing to enter into a Reliance Agreement to assign another IRB as the Reviewing IRB for multi-center research. The Reliance Agreement can be a Master Reliance Agreement that applies to all human subjects research involving two or more sites, or it can apply to a single study. Increasingly, funding agencies and federal regulations (the Final Rule taking effect January 20, 2018) will require a single IRB (sIRB) for multi center research.
NIH Mandate for a Single IRB
As of May 25, 2017,the NIH has mandated that all domestic sites participating in multi-center research studies use a single IRB (sIRB). The Final NIH Policy on the Use of a Single Institutional Review Board for Multi- Site Research will apply to all competing grant applications for due dates on or after January 25, 2018. For R&D contracts, the policy will apply to all solicitations issued on or after this effective date." The NIH uses the term sIRB to distinguish between IRBs (generally for-profit) that are structure to serve as the central IRB for multi-center studies and institution-based IRBs whose primary function is to serve the investigators at that institution. The policy was originally scheduled to take effect as of May 25, 2017 but NIH has issued an extension of the date for implementation which moves the effective date back until January 25, 2018.
Final Rule and Single IRBs
The Final Rule: Federal Policy for the Protection of Human Subjects issued January 19, 2017 includes a mandate for single IRB review for cooperative research (federally-funded research taking place at two or more institution). The Final Rule will take effect as of January 20, 2018 after which, all federal agencies that use the Common Rule will adhere to the regulations related to cooperative research (see "Regulatory and Literature Resources" below).
Procedures for Relying on an sIRB
CHOP will be the Reviewing IRB (sIRB): What needs to happen?
In general, the CHOP PI will first submit their study to the CHOP IRB in eIRB. Usually, the Reviewing IRB must grant approval of the protocol before another institution will agree to cede oversight. Other sites can then be added with an amendment. There are, however, exceptions where this can occur with initial approval of the study at CHOP.
The CHOP IRB has created a toolkit for CHOP investigators, which includes all the information about the process. Below are the components of the toolkit:
CHOP PI Toolkit
- Getting Started includes information about starting the discussion with the other site(s), materials to send to the external site and the submission to the CHOP IRB.
- The Intro Letter to the Outside Institution is a template CHOP investigators can customize and send to the other site(s). The letter explains the process of relying on the CHOP IRB.
- The Principal Investigator Responsibilities document provides a reviews the responsibilities for both Principal Investigators (at CHOP and the relying site) to assure compliance with all applicable regulations and protocol responsibilities.
- A stand-alone IRB Authorization Agreement or, if the study falls under one of CHOP's Master Reliance Agreements, the determination form (see below), needs to be signed by both institutions. The form outlines both the Reviewing IRB’s and the Relying Institution’s responsibilities.
- The Relying Site Progress Report allows the CHOP team to collect each site’s progress report (e.g. number of subjects enrolled) and submit this information to the CHOP IRB.
CHOP will rely on an external sIRB: What needs to happen?
Even after the external sIRB has approved the research, no human subjects research may begin at CHOP until a number of steps are completed. The CHOP IRB must agree to cede review to the sIRB, the CHOP IRB must confirm that the consent form aligns with CHOP's requirements, CHOP Ancillary Committees may need to review and approve the study - the IBC, Conflict of Interest Committee, etc. - and the CHOP Institutional Official will need to sign off on the agreement.
- Complete the CHOP eIRB Application: The CHOP investigator is required to complete an abbreviated eIRB application (check "Research Study involving CHOP reliance on an outside reviewing IRB") that includes amongst other things, a listing of study personnel, study funding, required ancillary committees (e.g., Pharmacy, Radiology, etc.), the recruitment plan (specific to CHOP), the protocol, the consent form as approved by the Reviewing IRB, the approval letter from the Reviewing IRB, and the signed IAA or determination form from the reviewing institution (if available). The investigators listed in the eIRB application also need to submit study-specific conflict of interest disclosures.
- Revise the Consent Form for Use at CHOP: The consent form approved by the Reviewing IRB for the main site must be adapted for use at CHOP and must conform to institutional requirements. To ensure that the Reviewing IRB includes all of the CHOP-required elements, the IRB has created instructions for the CHOP investigator and the Reviewing IRB which are outlined below.
- Finalize the Institutional Sign-Off: After the eIRB application is complete, all ancillary approvals are issued and an approved consent form has been uploaded that conforms to CHOP's requirements, the agreement to cede review can be finalized. A stand-alone IRB Authorization Agreement or, if the study falls under one of CHOP's Master Reliance Agreements, the determination form ceding review to the external IRB can be finalized (see below). The CHOP IRB will issue a letter to the CHOP investigator indicating that CHOP has ceded review to the external IRB.
- During the Study: Keeping the eIRB Application Up to Date: Although the CHOP IRB does not provide any oversight when an external IRB is the Reviewing IRB, the CHOP human subjects protection program remains responsible for all research activities that take place at CHOP. The CHOP Office of Research Compliance requires that all amendments and continuing reviews continue to be uploaded into eIRB to ensure that the study approval hasn't lapsed and that the only the most current, approved documents are being used.
Consent Form Requirements when Relying on an External IRB
The CHOP IRB cannot issue final approval to rely on an external IRB until the consent form includes all institutionally required elements. When CHOP serves as the IRB of record, the consent forms issued to the relying sites will incorporate the Relying Site's requirements. A pdf with the complete instructions for consent forms for CHOP and Penn can are included below. In brief, the requirements involve the following elements:
- Identification of CHOP as a research site;
- Inclusion of a CHOP contact for Emergencies;
- The HIPAA language must include CHOP as one of the institutions that will have access to PHI;
- The name and contact information for the CHOP investigator needs to be provided for withdrawal of permission;
- Contact information for the CHOP Office of Research Compliance must be included for subjects' questions;
- If injury compensation language is included in the consent form, then it must match CHOP's institutional requirements;
- The signature page must make clear that the subject is agreeing to allow CHOP to use and share health information (and not just the Reviewing IRB’s institution.
CHOP and Penn IRB Consent Form Requirements
- CHOP Consent Form Requirements: Instructions for the Investigators and the Reviewing IRB (2017)
- Penn IRB | Reliance Agreement Guidance – Requirements for External Consent Templates.
Master Reliance Agreements
Negotiating a Reliance Agreement can take weeks to months. To speed up the process, CHOP has entered into several Master Reliance agreements. Currently, there are Master Reliance Agreements with the University of Pennsylvania, the CIRB at the National Cancer Institute and with a consortium of pediatric academic institutions.
Research Conducted at both the University of Pennsylvania and CHOP
The CHOP IRB has had a Master Reliance Agreement with the University of Pennsylvania since 2005. The most recent agreement was executed December 5, 2016. Hundreds of studies have been included under this agreement benefitting both IRBs and reducing the burden on the CHOP and Penn investigators.
The process works by having the overall PI request that one of the IRBs – either Penn IRB or the CHOP IRB – serve as the Reviewing IRB for both institutions. The request can be made at the time of the initial submission for approval or as part of an amendment later. Research that takes place at Pennsylvania Hospital may also be included under this agreement.
If the CHOP IRB is to be the Reviewing IRB, the CHOP investigator submits the study (or amendment to add the University of Pennsylvania as a site) to the CHOP IRB (in eIRB) and indicates in the application that this is a multi-center study for which "CHOP will serve as the reviewing IRB for one or more other institutions". The completed Penn-CHOP determination form, signed by the investigator, needs to be attached to the application. If the CHOP IRB agrees to serve as the Reviewing IRB, then an IRB chair or designee signs the determination form and forwards it to the the Penn IRB.
If the Penn IRB is to be the Reviewing IRB, the investigator first submits to the Penn IRB (including the completed Penn-CHOP determination form, signed by the investigator). If the Penn IRB agrees to be the Reviewing IRB and signs the determination form, the CHOP PI needs to submit the study and the determination form (now signed by the investigator and the Penn IRB) to the CHOP IRB as a "Research Study involving CHOP reliance on an outside reviewing IRB". This is an abbreviated application in eIRB. Once CHOP agrees to cede review to the Penn IRB, an IRB chair or designee signs the determination form. See the section "If CHOP is asked to cede oversight to an external IRB: What needs to happen?" below for more information.
The Penn-CHOP Determination Form should be completed by the CHOP or Penn investigator requesting that their home institution's IRB serve as the IRB of record (Reviewing IRB). The signed and completed determination form should be included with the IRB application to whichever Institution (CHOP or Penn) that is being proposed to serve as the Reviewing IRB. If that IRB agrees to serve as the Reviewing IRB, a copy of the signed determination form will be forwarded to both the PI and to the Relying IRB.
For those interested, the Penn-CHOP Master Reliance Agreement that governs the relationship and interactions between the IRB at CHOP and the IRB at Penn is available for download and review.
Research reviewed by the NCI Pediatric Central IRB (CIRB)
CHOP has had a long-standing Master Reliance Agreement with the National Cancer Institute Central IRB. Prior to 2011, the NCI Pediatric CIRB used a facilitated review model. Since 2011, first as a pilot program and then as a widely-implemented program, the Pediatric CIRB has served as the Reviewing IRB for COG clinical trials. The CHOP IRB issues a letter accepting the Pediatric CIRB as the Reviewing IRB; there isn't a determination form that must be completed. The investigator is responsible for ensuring that the consent form has been edited so that it complies with CHOP's institutional requirements.
- CIRB-CHOP Institutional Authorization Agreement and Division of Responsibilities
- See consent form requirements (above) for editing the CIRB model consent so that it includes CHOP required language and meets all other CHOP requirements.
Master Common Reliance Agreement with Other Pediatric Institutions
CHOP has had numerous reliance agreements for research conducted at other pediatric institutions. As of May 2014, the Boston Children's Hospital, Cincinnati Children's Hospital and CHOP entered into an Master Reliance Agreement for research involving two or more of the institutions. This agreement was then modified and adopted by the other PEDSnet sites. Having a Master Reliance Agreement avoids the need to negotiate individual agreements when two or more of signatories participate in a study together. Aside from the 9 PEDsnet sites, 12 additional pediatric institutions or universities have signed on to participate in this agreement. For each study, a determination form must be completed, on which both the reviewing and relying site agree to apply the master reliance agreement to this particular study.
- Children's Hospital of Philadelphia (CHOP)
- Boston Children’s Hospital (BCH)
- Cincinnati Children’s Hospital and Medical Center (CCHMC)
- Children’s Hospital of Colorado
- Lurie Children's Hospital of Chicago
- Nationwide Children’s Hospital
- Seattle Children’s Hospital
- St Louis Children’s Hospital (Washington University)
- The Nemours Foundation
- Children's Healthcare of Atlanta
- Children’s Hospital Los Angeles
- Children’s Mercy Kansas City
- Children’s National Medical Center (CNMC)
- Dayton Children's Hospital
- Indiana University (Riley Children's Hospital)
- Stanford University
- University of Kentucky
- University of California, Davis
- Massachusetts General Hospital
- University of Utah (including Primary Children's)
- University of Alabama at Birmingham (including The Children's Hospital of Alabama)
- University of Nebraska Medical Center
The Master Common Reliance Agreement Determination Form should be completed by the PI at the site of the Reviewing IRB, signed by the PI's IRB representative and then forwarded to each Relying Site to obtain their institutional agreement and signature.
Reliance Agreements for a Single Study
When a Master Reliance Agreement is not in place, a Reliance Agreement must be executed for each study where CHOP's IRB or the external site's IRB will serve as the sIRB..
CHOP Standard IRB Reliance Agreement
When CHOP serves as the Reviewing IRB and the Relying Site is not a signatory to one of the several Master Reliance Agreements, the standard CHOP Authorization Agreement template should be used. The typical situation is where the CHOP PI is the overall study PI and the PI is requesting that the CHOP IRB serve as the Reviewing IRB for one or more Relying Sites. The CHOP IRB will assume this responsibility provided that the other site is registered with OHRP and has an FWA and agrees to the delegation of responsibility as outlined in the agreement.
When another external site's IRB proposes to serve as the Relying IRB, their standard Reliance Agreement is usually used. However, some IRBs do not have an standard Reliance Agreement. In these situations, the CHOP standard Reliance Agreement may be used as is, or in modified form. The external Reviewing IRB must sign the IRB Authorization Agreement before it is sent to CHOP for signature. The investigator should consult the IRB Director and request that she contact the Reviewing IRB to negotiate the agreement.
Regulatory and Literature Resources
45 CFR 46.114 Cooperative Research
- (a) Cooperative research projects are those projects covered by this policy that involve more than one institution. In the conduct of cooperative research projects, each institution is responsible for safeguarding the rights and welfare of human subjects and for complying with this policy.
- (b)(1) Any institution located in the United States that is engaged in cooperative research must rely upon approval by a single IRB for that portion of the research that is conducted in the United States. The reviewing IRB will be identified by the Federal department or agency supporting or conducting the research or proposed by the lead institution subject to the acceptance of the Federal department or agency supporting the research.
- (2) The following research is not subject to this provision:
- (i) Cooperative research for which more than single IRB review is required by law (including tribal law passed by the official governing body of an American Indian or Alaska Native tribe); or
- (ii) Research for which any Federal department or agency supporting or conducting the research determines and documents that the use of a single IRB is not appropriate for the particular context.
- (c) For research not subject to paragraph (b) of this section, an institution participating in a cooperative project may enter into a joint review arrangement, rely on the review of another IRB, or make similar arrangements for avoiding duplication of effort.
- OHRP webpage - Use of a Central Institutional Review Board
- FDA Guidance: Using a Central IRB Review Process in Multicenter Clinical Trials
- Flynn KE, et al. Using Central IRBs for Multicenter Clinical Trials in the United States. PLoS One. 2013;8(1):e54999.
- Millum & Menikoff. Streamlining ethical review. Ann Intern Med. 2010, Nov 16;153(10):655-7.
- Wagner et al. Costs and benefits of the national cancer institute central institutional review board. J Clin Oncol. 2010, Feb 1;28(4):662-6.
- Stark et al. Variation among institutional review boards in evaluating the design of a multicenter randomized trial. J Perinatol. 2010, Mar;30(3):163-9.
- Menikoff J. The Paradoxical Problem with Multiple-IRB Review. N Engl J Med. 2010, Oct 13;363(17):1591-3.
- Dilts et al. Steps and time to process clinical trials at the Cancer Therapy Evaluation Program. J Clin Oncol. 2009, Apr 10;27(11):1761-6.
Resources for NIH Policy on use of a Single IRB
- NIH webpage contains links to the policy, FAQs and other resources Clinical Research Policy - IRB Review. NIH Single IRB (sIRB) Policy
- (NIH) Accelerating Clinical Research by Streamlining Multi-Site Review of Human Subjects Research
- Final NIH Policy on the Use of a Single Institutional Review Board for Multi- Site Research
- Frequently Asked Questions about the NIH policy on use of a single IRB
- From the NEJM Dec 15, 2016: NIH Policy On Single-IRB review – A New Era in Multicenter Studies