Chapter 3: Reliance Agreements and Engagement in Research

An IRB reliance agreement is an arrangement in which one IRB acts as the Reviewing IRB on behalf of other institutions – referred to as Relying IRB(s). A reliance agreement defines the roles and responsibilities of each organization collaborating on a research project.

When a study is funded by U.S. Department of Health and Human Services (HHS) and National Institute of Health (NIH), additional documentation may be required in an agreement.

Reliance agreements vary in scope, terms, and terminology. Among the commonly used reliance agreements are:

• Memoranda of Understanding (MOU)
• IRB Authorization Agreements (IAA)*
• Master Reliance Agreement (MRA)
• Collaborative Review Agreement (CRA)
• Single IRB (sIRB) Reliance Agreement
• Central IRB Agreement (e.g. NCI’s CIRB)

Refer to Appendix C.

USC As Reviewing IRB

The Reviewing IRB acts as the “IRB of Record” by performing the review of human subjects research for the institutions/organization involved in the reliance agreement. USC IRB will act as the single IRB (sIRB) for non-exempt full board multi-site studies of no more than 5 participating US sites (including USC) due to limited resources. Exempt multi-site studies using the sIRB model will be considered on a case by case basis. Specific exceptions to the mandate may apply. The responsibilities of reviewing IRB and relying sites are detailed in the reliance agreement. The agreement will include the applicable responsibilities listed below and any applicable requirements set forth by the Association for the Accreditation of Human Research Protection Programs (AAHRPP) in Standard I-9. Specific exceptions to the NIH mandate may apply.

When USC is serving as the IRB of record for a multi-site study, or single IRB, the Overall Principal Investigator / Lead Primary Investigator is responsible for the communication plan, overall conduct of the study, and regulatory compliance as described in the following guidance: Overall Principal Investigator/Lead Study Team Guidance and Checklist. Relying sites are given contact information for a designated USC IRB analyst dedicated to providing guidance to the lead USC study teams and relying sites.

When an agreement is required an IRB application must be completed.

Responsibilities of the Reviewing IRB

• • • Initial submission review, and the review of the following for all sites:
      • reportable events
      • continuing review
      • amendments to previously approved research including submission of;
        • protocol changes requiring full board review
        • addition of study sites and personnel changes via expedited review
          (Refer to Chapter 6.3 Expedited Review)
    • Ensure IRB approval criteria are satisfied by all participating sites, including local context information provided by relying institutions
    • Review consent forms, when applicable
    • Make Privacy Board determinations per HIPAA, when applicable
    • Consider conflict of interest determinations, including any management plans, relating to the research and ensure plans are incorporated into IRB review as applicable
    • Notify PI, Sponsor, and federal agencies, as appropriate of IRB decisions and action, and ensure appropriate communication plan for dissemination between sites
    • Maintain appropriate IRB records and documents relating to the IRB review, and make records available to relying institutions, upon request
    • Notify the relying institutions of any of the following, as relevant:
      • Serious and/or continuing noncompliance, suspensions, and/or
      • terminations
      • Audits, including findings and corrective actions
      • Reporting to a federal agency
      • Communication with regulatory agencies
    • Provide relevant minutes of IRB meetings to the relying institution/organization
      upon request.

Relying IRB

A Relying IRB defers to a review and approval of human research provided by an IRB that is unaffiliated with the institution. The responsibilities of the Relying IRB and the Reviewing IRB must be documented in an agreement. The agreement will include the applicable essential requirements set forth by AAHRPP Standard I-9.

The Relying IRB reviews and approves local ancillary services and is responsible for local institution-specific compliance issues.

Responsibilities of the Relying IRB

• • • • Ensure research personnel are appropriately qualified and meet relying institution standards for eligibility to conduct research, including but not limited to human subjects protection training and collection and maintenance of conflict of interest disclosure forms
      • Provide local context information to the reviewing IRB and ensure required information is incorporated into IRB-approved documents
      • Provide local ancillary approvals to the reviewing IRB
      • Ensure research personnel are notified of their responsibilities when
        conducting research pursuant to a reliance agreement
      • Ensure compliance with the reviewing IRB determinations and requirements, applicable federal regulations, and all applicable state and local laws and institutional requirements
      • Ensure appropriate monitoring of research and perform reviewing IRB-directed audits upon request
      • Establish a process for reviewing conflicts of interest and creating management plans when appropriate
      • Document and notify the reviewing IRB of any of the following which relates to research:
        • PI and personnel changes
        • Changes that require ICF and HIPAA revision
        • Serious and/or continuing noncompliance
        • Restriction/suspension of research activities
        • Audits, including findings and corrective actions
        • Communication with regulatory agencies
        • Legal claims
        • Research misconduct
      • Receive notifications of issues from the reviewing IRB and take additional local action, if applicable

USC Investigator Relying on An External IRB

A USC investigator who is engaged in research and relying on an independent or external IRB must submit a Ceded Review application in iStar (iStar item 1.1). Refer to Section 4.2 Engagement in Research. The submission must include all required ancillary committee reviews (e.g. Radiation Safety, Biosafety) that apply.

The Ceded Review application must include all study documents approved by the reviewing IRB of record. The USC IRB will review the Ceded Review submission to verify that all requirements have been met. Required documentation may vary based upon the sponsor and/or agreement platforms such as SMART IRB.

The investigator cannot conduct study activities until a Reliance Agreement or IRB Authorization Agreement (IAA) is fully executed.

An acknowledgment letter will be issued by the USC IRB indicating that the study has been cleared to begin at USC.

USC investigators must submit reportable events and participant complaints to the reviewing IRB as agreed upon, and to the USC IRB as described in Section 8.8 Reportable Events and Section 8.9 Participant Complaints.

An amendment must be submitted to the USC IRB if any of the following changes occur:

• Addition of investigators
• New conflict of interest for investigators
• Addition of special populations (adults who are not competent to consent or minors)
• Addition of LA General Medical Center as a study location
• Changes in HIPAA authorization forms or waivers
• Changes in funding or addition of research procedures that require review by other USC committees (Clinical Trials Office, Department of Contracts & Grants, Biosafety, and Radiation Safety Committee)

When Relying on An External IRB That Is Not AAHRPP Accredited
USC will consider the qualifications of an external IRB that is not AAHRPP accredited if such an arrangement is beneficial to USC, its investigators, and/or its research participants. The Principal Investigator must submit a Ceded Review application in iStar (iStar item 1.1) As per OHRP Guidance, an IRB Authorization Agreement will establish and clearly delineate roles and responsibilities of each party. The reviewing IRB will be required to meet the following criteria based on the nature of the study.
For minimal risk research, USC IRB may:

• • Obtain an assurance from the non-accredited IRB that it will conduct its review consistent with the applicable ethical standards and regulations, and that it will report any regulatory violations or investigations of the reviewing IRB by regulatory agencies, such as OHRP, the FDA, or regulatory agencies in other countries.
  • Request the reviewing IRB to attest that it has completed its
    own internal quality review process, such as use of AAHRPP’s
    Evaluation Instrument for Accreditation to conduct a self-assessment or completion of the US FDA’s self-evaluation (Checklist for IRBs: https://www.fda.gov/media/99271/download and/or the OHRP QA Self- Assessment Tool:
    https://www.hhs.gov/ohrp/sites/default/files/ohrp/education/qip/ohrpqatool.pdf).

IRB Reliance Agreement With USC

Descriptions of the most commonly used agreements are provided below.

IRB Authorization Agreement (IAA)

An IRB Authorization Agreement is one type of IRB reliance agreement typically used between just two institutions. It is recommended when several non-USC sites, with or without their own IRBs, rely on USC’s IRB, or vice versa. SMART IRB will be used as the primary reliance agreement when USC IRB is serving as the IRB if record. If the relying institution is not associated with SMART IRB, the USC IRB Authorization Agreement form will be completed. 

The IRB Authorization Agreement may be written to cover one research project, several research projects on a case-by-case basis, or to cover a program of research.

Establishing an IRB Authorization Agreement
IRB submissions for establishing an IRB Authorization Agreement must include the research sites external to USC or CHLA. Submit an application for “Research Protocol or Study on Human Subject” (iStar item 1.1) and include any site not affiliated with USC or CHLA where research will be conducted. When ceding review and approval to an external IRB select “Ceded Review” (iStar item 1.1).
IRB Associate Directors are authorized to sign IRB authorization agreements (subject to limitations defined by university policy. (Provost Signature Authorization)

• • NIH Single IRB Mandate

    NIH funded research that is carried out at more than one site in the United States must be overseen by a single IRB. This NIH policy applies to grant applications received on or after January 25, 2018. This mandate applies to non-exempt research in which all sites are performing the same activities. Specific exceptions to the mandate may apply. 
    The NIH policy also requires that a “communication plan” be included in grant application/proposals. The applicant/offeror is expected to submit a communication plan describing the use of an sIRB that will be selected to serve as the IRB of record for all study sites. The plan should include a statement confirming that participating sites will adhere to the sIRB policy and describe how communications between sites and sIRB will be handled. In addition, a budget for sIRB fees will be required as part of the grant application.

    • NIH Policy on the Use of a Single IRB (sIRB)
    • Requisites for Single IRB

    USC IRB will act as the single IRB (sIRB) for full board multi-site studies of no more than 5 participating US sites (including USC) due to limited resources. Exempt multi-site studies using the sIRB model will be considered on a case by case basis. In accordance with OHRP Guidance, an agreement must state the responsibilities of both parties. The agreement will include the applicable essential requirements set forth by AAHRPP Standard I-9.

  • Cooperative (Multi-site) Research

    Beginning January 2020 USC participation in any cooperative multi-site research must rely upon approval by a single IRB for that portion of the research that is conducted in the United States. The following is regulation 45 CFR 46.114(b):

    (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.

  • National Cancer Institute (NCI) Central IRB (CIRB)

    USC is participating in the National Cancer Institute (NCI) Central IRB (CIRB). CIRB is the IRB of Record responsible for review of the study as well as review of local context issues for participating sites. Local policy, conflict of interest, HIPAA authorization, and ancillary committee approvals are still the responsibility of the relying IRB (USC).
    For research reviewed by NCI, the Clinical Investigator Support Office at USC Comprehensive Cancer Center (CISO) typically provides review of scientific merit, resources and financial aspects of the study.

  • SMART IRB

    USC is a signatory to the SMART IRB Master Reliance Agreement that is supported by NIH funding and recommended by NIH policy for single IRB review. The agreement is designed to harmonize and streamline the IRB review process for multisite studies, while ensuring a high level of protection for research participants. When possible, USC will use the SMART IRB agreement as the basis for reliance when serving as the sIRB or being a relying IRB of a SMART IRB study.

• Engagement in Research

  The USC IRBs define engagement in research according to OHRP’s 2008 guidance on the engagement of Institutions in research and OHRP’s 2011 Correspondence on “Non- engaged Scenarios”.
  An Institution becomes “engaged” in human subjects research when its employees or agents (all individuals performing institutionally-designated activities or exercising institutionally-delegated authority or responsibility, including faculty and students):

  1. Obtains information or biospecimens through intervention or interaction with the individual, and uses, studies, or analyzes the information or biospecimens; or
  2. Obtains, uses, studies, analyzes, or generates identifiable private information or identifiable biospecimens.

  An Institution is automatically considered to be “engaged” in human subjects research whenever it receives a direct HHS award to support such research. In such cases the awardee’s Institution bears ultimate responsibility for protecting human subjects under the award.
  IMPORTANT NOTE: The USC IRBs require review by a USC IRB and by the IRB(s) at other location(s) (if the other Institution is “Engaged in the Research”) regardless of funding, unless an IRB Authorization Agreement (IAA) is required or obtained. (See Cooperative (Multi-Site) Research.

• Engaged Research

  In general, Institutions are considered engaged in an HHS-conducted or -supported non- exempt human subjects research project (and, therefore, would need to hold or obtain OHRP-approved FWAs and certify IRB review and approval to HHS) when the involvement of their employees or agents in that project includes any of the following:

  • Institutions that receive an award through a grant, contract, or cooperative agreement directly from HHS for the non-exempt human subjects research (awardee Institutions), even where all activities involving human subjects are carried out by employees or agents of another Institution
  • Institutions whose employees or agents intervene for research purposes with any human subjects of the research by performing invasive or noninvasive procedures. Examples of invasive or noninvasive procedures include drawing blood; collecting buccal mucosa cells using a cotton swab; administering individual or group counseling or psychotherapy; administering drugs or other treatments; surgically implanting medical devices; utilizing physical sensors; and utilizing other measurement procedures
  • Institutions whose employees or agents intervene for research purposes with any human subject of the research by manipulating the environment. Examples of manipulating the environment include controlling environmental light, sound, or temperature; presenting sensory stimuli; and orchestrating environmental events or social interactions.
  • Institutions whose employees or agents interact for research purposes with any human subject of the research. Examples of interacting include engaging in protocol dictated communication or interpersonal contact; asking someone to provide a specimen by voiding or spitting into a specimen container; and conducting research interviews or administering questionnaires.
  • Institutions whose employees or agents obtain the informed consent of human subjects for the research
  • Institutions whose employees or agents obtain for research purposes identifiable private information or identifiable biological specimens from any source for the research. It is important to note that, in general, Institutions whose employees or agents obtain identifiable private information or identifiable specimens for non- exempt human subjects research are considered engaged in the research, even if the Institution’s employees or agents do not directly interact or intervene with human subjects. In general, obtaining identifiable private information or identifiable specimens includes, but is not limited to:
    • observing or recording private behavior
    • using, studying, or analyzing for research purposes identifiable private
      information or identifiable specimens provided by another Institution
    • using, studying, or analyzing for research purposes identifiable private information or identifiable specimens already in the possession of the investigators

• In general, OHRP considers identifiable private information and identifiable biospecimens as defined in 45 CFR 46.102(e)(6) when the identity of the subject is or may readily be ascertained by the investigator or associated with the information or biospecimen.

• NOT Engaged Research

  (For examples see the OHRP 2008 Guidance for Engaged Research)
  Institutions would be considered not engaged in an HHS-conducted or -supported non- exempt human subjects research project (and, therefore, would not need to hold an OHRP-approved FWA or certify IRB review and approval to HHS) if the involvement of their employees or agents in that project is limited to one or more of the following examples. The following describes the types of institutional involvement that would make an Institution not engaged in human subjects research;

  1. Institutions whose employees or agents perform commercial or other services for investigators provided that all of the following conditions also are met:
     • the services performed do not merit professional recognition or
       publication privileges
     • the services performed are typically performed by those Institutions for
       non-research purposes
     • the Institution’s employees or agents do not administer any study
       intervention being tested or evaluated under the protocol
  2. Institutions whose employees or agents provide medical services that are dictated by the protocol and would typically be performed as part of routine clinical care and/or follow-up, are considered “not engaged” in research provided that all of
     the following conditions also are met:
     • the Institution’s employees or agents do not administer the study interventions being tested or evaluated under the protocol
     • the clinical trial-related medical services are typically provided by the Institution for clinical purposes
     • the Institution’s employees or agents do not enroll subjects or obtain the informed consent of any subject for participation in the research
     • when appropriate, investigators from an Institution engaged in the research retain responsibility for:
       • overseeing protocol-related activities
       • ensuring appropriate arrangements are made for reporting
         protocol-related data to investigators at an engaged Institution, including the reporting of safety monitoring data and adverse events as required under the IRB-approved protocol

     Note that Institutions (including private practices) not initially selected as research sites whose employees or agents administer the interventions being tested or evaluated in the study—such as administering either of two chemotherapy regimens as part of an oncology clinical trial evaluating the safety and effectiveness of the two regimens—generally would be engaged in human subjects research (see scenario B.(3) in OHRP guidance for a limited exception). If such an Institution does not have an FWA, its employees or agents may be covered by the FWA of another Institution that is engaged in the research through completion of an Individual Investigator Agreement and/or IRB Authorization Agreement

  3. Institutions (including private practices) not initially selected as a research site whose employees or agents administer the study interventions being tested or evaluated under the protocol limited to a one-time or short-term basis (an oncologist at the Institution administers chemotherapy to a research subject as part of a clinical trial because the subject unexpectedly goes out of town, or is unexpectedly hospitalized), provided that all of the following conditions also are met:
     • an investigator from an Institution engaged in the research determines that it would be in the subject’s best interest to receive the study interventions being tested or evaluated under the protocol
     • the Institution’s employees or agents do not enroll subjects or obtain the informed consent of any subject for participation in the research
     • investigators from the Institution engaged in the research retain responsibility for:
       • overseeing protocol-related activities
       • ensuring the study interventions are administered in accordance
         with the IRB-approved protocol and
       • ensuring appropriate arrangements are made for reporting
         protocol-related data to investigators at the engaged Institution, including the reporting of safety monitoring data and adverse events as required under the IRB-approved protocol and
       • an IRB designated on the engaged Institution’s FWA is informed that study interventions being tested or evaluated under the protocol have been administered at an Institution not selected as a research site
  4. Institutions whose employees or agents:
     • inform prospective subjects about the availability of the research
     • provide prospective subjects with information about the research (which
       may include a copy of the relevant informed consent document and other IRB approved materials) but do not obtain subjects’ consent for the research or act as representatives of the investigators
     • provide prospective subjects with information about contacting investigators for information or enrollment and/or
     • seek or obtain the prospective subjects’ permission for investigators to contact them
  5. Institutions (schools, nursing homes, businesses) that permit use of their facilities for intervention or interaction with subjects by investigators from another Institution. Example would be a school that permits investigators from another Institution to conduct or distribute a research survey in the classroom.
  6. Institutions whose employees or agents release to investigators identifiable private information or identifiable biological specimens pertaining to the subjects of the research. Note that in some cases the Institution releasing identifiable private information or identifiable biological specimens may have institutional requirements that would need to be satisfied before the information or specimens may be released, and/or may need to comply with other applicable regulations or laws. In addition, if the identifiable private information or identifiable biological specimens to be released were collected for another research study covered by 45 CFR part 46, then the Institution releasing such information or specimens should:
     • ensure that the release would not violate the informed consent provided by the subjects to whom the information or biological specimens pertain (under 45 CFR 46.116), or
     • if informed consent was waived by the IRB, ensure that the release would be consistent with the IRB’s determinations that permitted a waiver of informed consent under 45 CFR 46.116 (c) or (d)

     Note that, in general, the Institutions whose employees or agents obtain the identifiable private information or identifiable biological specimens from the releasing Institution would be engaged in human subjects research.

  7. Institutions whose employees or agents:
     • obtain coded private information or human biological specimens from
       another Institution involved in the research that retains a link to individually identifying information (such as name or social security number), and
     • are unable to readily ascertain the identity of the subjects to whom the coded information or specimens pertain because, for example:
       • the Institution’s employees or agents and the holder of the key enter into an agreement prohibiting the release of the key to those employees or agents under any circumstances
       • the releasing Institution has IRB-approved written policies and operating procedures applicable to the research project that prohibit the release of the key to the Institution’s employees or agents under any circumstances, or
       • here are other legal requirements prohibiting the release of the key to the Institution’s employees or agents

     For purposes of this document, coded means that:

     • identifying information (such as name or social security number) that would enable the investigator to readily ascertain the identity of the individual to whom the private information or specimens pertain has been replaced with a number, letter, symbol, and/or combination thereof (the code), and
     • a key to decipher the code exists, enabling linkage of the identifying information to the private information or specimens

     Although this scenario resembles some of the language in OHRP’s Guidance on Research Involving Coded Private Information or Biological Specimens, it is important to note that OHRP’s Guidance on Research Involving Coded Private Information or Biological Specimens addresses when research involving coded private information or specimens is or is not research involving human subjects, as defined in 45 CFR 46.102(e)(1)
     (see http://www.hhs.gov/ohrp/policy/cdebiol.html).
     The Guidance on Engagement of Institutions in Human Subjects Research (2008) should only be applied to research projects that have been determined to involve human subjects and that are not exempt under HHS regulations at 45 CFR 46.104.

  8. Institutions whose employees or agents access or utilize individually identifiable private information only while visiting an Institution that is engaged in the research, provided their research activities are overseen by the IRB of the Institution that is engaged in the research.
  9. Institutions whose employees or agents access or review identifiable private information for purposes of study auditing (a government agency or private company will have access to individually identifiable study data for auditing purposes).
  10. Institutions whose employees or agents receive identifiable private information for purposes of satisfying U.S. Food and Drug Administration reporting requirements.
  11. Institutions whose employees or agents author a paper, journal article, or presentation describing a human subjects research study.

  Investigators should review all information included in the OHRP 2008 Guidance for Engaged Research. For additional questions or further clarification, investigators can contact the IRB.

• IRB Approval of USC Research at a Non-USC Site

  USC faculty/staff/students conduct research at other sites, both domestic and international. When USC is engaged in research with another Institution, alternative arrangements for IRB review may be established in an agreement. Section 3.1 – IRB Reliance Agreements
  If non-USC sites are engaged in research (45 CFR 46) and have their own IRB(s) or equivalent ethics board, the USC IRB expects the non-USC sites to obtain their own IRB review for research carried out at their site, unless an IRB Authorization agreement is obtained.
  When conducting research at a non-USC site, USC investigators are required to provide the following information in the iStar application:

  • Site name and address
  • Description of activities that will take place at the site
  • Whether the non-USC site has an IRB
  • Confirmation of the IRB’s and/or equivalent authority’s approval to conduct the research for non-exempt research.
  • Approved informed consent form(s) and recruitment material, if appropriate

To prevent lapses in human subject protection, it is generally preferred, when possible, that the same IRB retain oversight responsibility throughout the conduct of a research project. Transfers may occur for a number of different reasons. The appropriate steps and considerations for oversight transfer will depend on the specific circumstances, including the reasons for the transfer and the potential risk to human subjects.

Transfer of IRB oversight may occur in any of the following circumstances, including cessation of IRB operations, consolidation of multiple IRBs into a single IRB, temporary inability of an IRB to meet its obligations, or as the result of IRB non-compliance.

If a study comes to USC with approval from a registered IRB – USC may accept the approval until the time of continuing review. If there are concerns, USC will conduct a review. If work was done under no IRB or a non-registered IRB, the study cannot be conducted until a new submission is complete and approval is provided by USC IRB.

For further guidance refer to: “Guidance for IRBs, Clinical Investigators, and Sponsors Considerations When Transferring Clinical Investigation Oversight to Another IRB”

Disaster Response

The USC Office of Research has developed a Business Continuity Plan that contains guidance for the oversight of the functions of the USC Human Research Protection Program in the event of a disaster. Depending upon the breadth of a disaster, regulatory functions may be impacted. Transfer of oversight to an unaffected IRB may be required to maintain protection of human research subjects in ongoing research.

The Business Continuity Plan contains emergency response and process-specific recovery strategies for IRB functions and associated communications. Additional guidance from OHRP is available: “Effects of Disasters on Human Research Protections Programs Guidance.