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Multicenter Research & Single IRB

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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.

Topics that need to be agreed upon include who reviews what (e.g. staff changes are still the responsibility of the relying institution), the exchange of information between the reviewing IRB and relying institution (e.g. IRB determinations, CoI management plans, unanticipated problems, reporting of serious or continuing non-compliance, suspension of a study or an investigator).

The agreements can be for a single research study or for multiple studies (e.g., a Master Reliance Agreement). A Master Reliance Agreement outlines all the general terms on roles and responsibilities. For individual studies under such a master reliance agreement, the reviewing IRB and relying institution can then agree that the agreement applies to that specific study (rather than negotiating an agreement for every single study).

The NIH mandates (for federally funded studies), and study consortia, some funding agencies, and industry sponsors have increasingly encouraged, the designation of central IRB to serve as the Reviewing IRB for all participating sites in multi-center research studies.

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. Information about each of the Master Reliance Agreements between CHOP and other groups or institutions can be found below. Increasingly, funding agencies and federal regulations (the Final Rule) will require a single IRB (sIRB) for multi center research.

At present, CHOP can only enter into reliance agreements to rely on another U.S.-based IRB. The information on this page therefore, applies to reliance agreements between institutions and IRBs located in the U.S.

The following sections provide information on:

  • The initial submission, consent requirements and cooperative updates for CHOP investigators who want to conduct research study that involves relying on an outside IRB ('Relying on an Outside IRB - How To')
  • The process when CHOP is the reviewing IRB. A PI toolkit helps CHOP investigators who want to add outside investigators to their study under the oversight of the CHOP IRB. Guides on how to use the CHOP IRB Reliance Portal (CHIRP) will aid outside investigators in establishing direct communication with the CHOP IRB ('Other Sites Relying on the CHOP IRB - How To').
  • Master Reliance Agreements CHOP has entered into (e.g. University of Pennsylvania, Drexel University, SMART IRB, PCIRB, and Columbia University (CU) for NAMDC research studies) and Reliance Agreements for a Single Study.
  • Regulatory requirements, such as the NIH and Final Rule Mandates, and other Regulatory and Literature Resources.

Definitions

  • External IRB: The IRB at another institution or an independent IRB. An external IRB must be registered with OHRP (and FDA if the research if FDA regulated) in order to serve as the reviewing IRB (IRB of record).
  • IRB Authorization Agreement (also referred to as a Reliance Agreement or Cooperative Agreement): An agreement between the institution conducting the research and the Reviewing IRB. 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 had a master reliance agreement in place since 2006.
  • Master Reliance Agreement: An agreement between two or more institutions or IRBs that can cover future research. Examples of Master Reliance Agreements include CHOP-Penn Master Reliance Agreement, SMART IRB Agreement, National Cancer Institute Central IRB Authorization Agreement. Typically, Master Reliance Agreements are used with determination forms or other mechanisms to document the implementation of the reliance agreement for specific studies (e.g. Determination Form, Cede Letter).
  • 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. For example, Penn and CHOP sign a determination form when one relies on the other's IRB for a specific 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 Institution or Relying Site: A hospital, clinic, doctor's office where research will take place and which will rely on an external IRB (Central IRB) 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: The IRB that is responsible for the review, approval and regulatory oversight of a multi-center research study and serving more than one site. The 'Reviewing' or 'Central' IRB is sometimes referred to as the IRB of Record.
  • sIRB: The Single IRB or Reviewing IRB for multi-center research.
  • Site PI: A principal investigator who is responsible for the conduct of the research at their Participating Institution.

Relying on an Outside IRB - How To

Even after the external sIRB has approved the research, no human subjects research may begin at CHOP until a number of steps are completed. For CHOP to 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, Pharmacy, etc. - and the CHOP Institutional Official (or designee) will need to sign off on the reliance documentation.

Yes. Here are the steps that need to be completed:

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 (e.g. disclose the CHOP PI's name and contact information, include the CHOP HIPAA and injury compensation language). 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 in "Consent Form Requirements when Relying on an External IRB" 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.

The CHOP IRB cannot issue final acceptance to rely on an external IRB until the consent form includes all institutionally required elements. When CHOP serves as the reviewing IRB, the consent forms issued to the relying sites will incorporate the Relying Site's requirements. PDFs with the complete instructions for consent forms for CHOP and Penn are 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

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. This also allows e.g. the Pharmacy to have access to the current Investigator's Brochure for drug trials.

Cooperative Update Submission
To submit such updates (amendment, continuing reviews, or reportable events), eIRB allows creation of a "New Cooperative Update" using a separate smartform. Multiple, separate Cooperative Updates can be active at once. The system includes functionality like document tracking and dedicated tools to assist with processing and communication between investigators and the IRB. The IRB has created a Job Aid (under 'eIRB Help') to facilitate the submission process.

 

Other Sites Relying on the CHOP IRB - How To

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.

The CHOP PI Toolkit contains:

  • 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.
  • For resources related to CHOP's IRB Reliance Portal (CHIRP) specifically, see the CHIRP accordion below.

For further guidance, see Principal Investigator Oversight of Multicenter Research.

CHIRP is the CHOP IRB's tool that allows investigators from external institutions who are relying on the CHOP IRB for IRB review to communicate directly with the CHOP IRB.

How does CHIRP Work?

  • With a full amendment to the study in eIRB, the CHOP investigator will add the new relying site(s). In addition to selecting the relying institution's name, the CHOP investigator must also provide the relying PI's name and email address.
  • The relying PI will receive an automated email when the CHOP investigator submits the full amendment in eIRB. This notification will include a link to the CHIRP portal (which can be accessed outside the CHOP firewall).
  • If the relying PI does not already have a CHIRP account, they will have to create a PI profile in CHIRP.
  • The relying PI then needs to provide site-specific information for the study in CHIRP and submit it to the CHOP IRB.
  • The CHOP IRB will receive and review the CHIRP application in eIRB.
  • The relying PI will receive an email with either stipulations (if there are any) or the link to the site-specific approval letter.
    • If stipulations are issued, the relying PI must make the necessary changes in and submit a response through CHIRP, until site approval is obtained.

The CHOP IRB has created guides for relying investigators:

  • The MS Authenticator Guidance for CHIRP provides step-by-step instructions for downloading and installing Microsoft Authenticator, to enable non-CHOP investigators relying on the CHOP IRB to log into the CHOP IRB Reliance Portal (CHIRP).
  • The CHIRP Portal User Guide provides instructions for CHOP investigators and relying site investigators on how to start a study in CHIRP and submit an initial request for reliance.
  • The CHIRP Portal Continuing Review User Guide provides instructions for CHOP investigators and relying site investigators on how to create a continuing review for studies using CHIRP.
 

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.

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.

The CHOP IRB entered into a Master Reliance Agreement with Drexel University in 2019. The process works similarly to the one described for Penn and CHOP above.

The Drexel-CHOP Determination Form should be completed by the CHOP or Drexel 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 Drexel) 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 Drexel-CHOP Master Reliance Agreement that governs the relationship and interactions between the IRB at CHOP and the IRB at Drexel is available for download and review.

SMART IRB was created to streamline the IRB reliance agreement process between institutions and is funded by the National Center for Advancing Translational Sciences (NCATS). SMART IRB was funded by the NIH to help facilitate single IRB review to comply with the NIH's mandate. The SMART IRB master reliance agreement facilitates the authorization agreement process between participating institutions. A list of the signatories to the SMART IRB agreement is available. CHOP is a signatory to the SMART IRB Agreement.

SMART IRB offers several options for documenting reliance between institutions for a specific research study. It is up to the Reviewing IRB to determine which of the following documentation methods will be used for a specific study:

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.

CHOP has entered into a master reliance agreement with Columbia University (CU) for NAMDC research studies. Columbia University will be the Reviewing IRB for these studies. The NAMDC Columbia University Central IRB Agreement Determination Form should be completed by the CHOP investigator requesting reliance on the CU IRB (Reviewing IRB). The signed and completed determination form must be uploaded into eIRB as part of the IRB application.

 

Reliance Agreements for a Single Study

When a Master Reliance Agreement is not in place, a single-study Reliance Agreement must be executed for each study. The agreement can designate either CHOP's IRB or the external site's IRB to serve as the Reviewing IRB (sIRB). Usually the Reviewing IRB is at the institution where the overall PI is located.

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. An agreement is needed with each site that will rely on CHOP. The CHOP IRB will assume this responsibility provided that the other sites are registered with OHRP and have an FWA and that each site 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 usually signs 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.

 

NIH and Final Rule Mandates

As of May 25, 2017,the NIH has mandated that all domestic sites participating in multi-center research studies (where each site will conduct the same protocol) use a single IRB (sIRB). The Final NIH Policy on the Use of a Single Institutional Review Board for Multi- Site Research applies to non-exempt human subjects research, whether supported through grants, cooperative agreements, contracts, or the NIH Intramural Research Program. It does not apply to career development, research training or fellowship awards. This policy applies to all competing grant applications (new, renewal, revision, or resubmission) with receipt dates on or after May 25, 2017. 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 moved the effective date back to January 25, 2018 (the policy is now in effect).

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 requirement for single IRB review for cooperative research took effect January 20, 2020. Learn more about the updates to the Common Rule and the Final Rule: Single IRB Requirement.

In the application/proposal for research funding, the applicant/offeror is expected to submit a plan describing the use of an sIRB that will be selected to serve as the IRB of record for all study sites. The IRB has developed Grant Template Language which can be used to describe the use of CHOP as the sIRB.

 

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.
 

Frequently Asked Questions

  1. An external IRB is the IRB of record for my study. Do I need to submit anything in eIRB, and if so, why?

    Yes. Even though the CHOP IRB may not have oversight over the study, CHOP's Human Subjects Protection Program (HRPP) still needs to know and track what human subjects research activities go on at the institution. In addition, the CHOP IRB must confirm that the consent form aligns with CHOP's requirements (e.g. HIPAA and injury compensation language), and CHOP Ancillary Committees may need to review and approve the study (e.g. the Investigational Pharmacy, Contracting, IBC, Conflict of Interest Committee, Medical Device Committee, etc.).

  2. Once I have submitted in eIRB and indicated that an external IRB is the reviewing IRB, do I have to wait for an acknowledgement before I can start my research, and if so, why?

    Yes. The CHOP IRB must confirm that the consent form aligns with CHOP's requirements (e.g. HIPAA and injury compensation language), and CHOP Ancillary Committees may need to review and approve the study (e.g. the Investigational Pharmacy, Contracting, IBC, Conflict of Interest Committee, Medical Device Committee, etc.). Once all the institutional requirements are met, the CHOP IRB will send a letter to accept the reliance on the outside IRB. Human subjects research at CHOP for that particular study cannot start until that letter has been issued and reliance documentation has been executed.

  3. If CHOP is relying on another IRB for my study, do I have to submit updates in eIRB, and if so, why?

    Yes. CHOP's Human Subjects Protection Program (HRPP) still needs to track what human subjects research activities go on at the institution. In addition, CHOP Ancillary Committees, such as the Investigational Pharmacy, need access to currently approved documents (such as the Investigator's Brochure).

  4. How do I submit Cooperative Updates?

    In the main study workspace for the study in eIRB, under the 'Create' header on the left side of the workspace, find the "New Cooperative Update" button. Clicking on it will open a new smartform. After the smartform has been completed by the investigator, using the "Submit Cooperative Update" activity will send the submission to the IRB. The IRB has created a Job Aid (under 'eIRB Help') to facilitate the submission process.

    Note: Multiple, separate Cooperative Updates can be active at once.

  5. Once I submit a cooperative update, do I have to wait for an acknowledgement before I can implement e.g. amendment changes?

    No. Once CHOP has accepted the reliance on an outside IRB, amendment changes can be implemented as soon as the reviewing IRB has approved the amendment.

  6. I'm writing a grant for a multi-center study and would like CHOP to be the Reviewing IRB. What is the process?

    Contact the IRB Director to discuss the grant requirements and sIRB logistical issues.

  7. What is CHIRP?

    CHIRP is the CHOP IRB's tool that allows investigators from external institutions who are relying on the CHOP IRB for IRB review to communicate directly with the CHOP IRB. See Single IRBs and IRB Reliance Agreements for more information.

  8. The relying PI for my study has received an email from CHIRP, but the link states 'The invite token is expired'! What do I do?

    This error can be resolved by having the external PI navigate to the CHIRP homepage, and request a password reset. Note: Each time a password reset is requested, a new automated email is issued. The new email will invalidate any prior emails, so the relying investigator should be sure to always use the most recent email.

  9. Do relying sites need to update their CHIRP application with investigators or their training(s)?

    Other than the relying PI and Study Coordinator, no. The CHIRP application asks relying sites to "Confirm that all study team members are in compliance with local institutional training requirements for human subjects research. (e.g. CITI training and/or other institution specific training)". Otherwise, any relying personnel-specific changes are the responsibility of the relying institution to manage.