Attachment A: Initial Considerations for Single IRB Review: Points to Consider

Attachment A:  Initial Considerations for Single IRB Review: Points to Consider

Approved by SACHRP October 26, 2016

Background

Given the increase in the number of sponsors who now require the use of a single institutional review board (IRB) review, many institutions are now challenged with serving as a single IRB for multisite research or relying on another IRB to review its research. The purpose of this document is to provide points to consider relating to the arrangement that is entered into where an institution cedes IRB review of research conducted at that institution to another IRB. The other IRB could be one at a similar institution (hospital, academic medical center, for-profit or non-profit institution) or an independent institutional review board that reviews, but does not conduct, research. The issues raised in this document are not intended to serve as a decision tool, but rather as a set of points to consider in making the decision whether to serve as a reviewing IRB or a relying institution. IRB administrators, institutional officials and investigators may find the information in this document a helpful resource in establishing and/or implementing this arrangement. As in any relationship, cooperation, collaboration and communication are critical to the success of the arrangement.

The premise of any of these reliance arrangements is that the reviewing institutional review boards will be subject to Federalwide Assurances and will follow the regulatory criteria for IRB review of research. Responsibilities of the relying institution will be based on the agreement and may vary from site to site. Both the reviewing IRBs and relying institutions have the responsibility of keeping track of the different obligations and responsibilities set forth in each IRB authorization agreement.

This document was developed with a focus on multi-site research conducted within the United States. However, many of the considerations for institutions and IRBs engaged in multisite research in the United States are applicable in the international context.

Definitions

For the purpose of this document the following are definitions for certain frequently used terms:

• Authorization Agreement - a written agreement between two or more institutions that is used to document the delegation of IRB review responsibilities. This agreement may also be referred to as a reliance agreement or cede review agreement.
• Cede review - the act of transferring IRB review and oversight.
• Reviewing IRB - the IRB of record performing review on behalf of one or more institutions, also referred to as the single IRB and/or central IRB.
• Relying Institution - the entity that agrees to rely upon the reviewing IRB.
• Sponsors and funders – generally refers to any entity that is supporting research and includes non-profit and for profit entities.

Points to Consider

1. What are some of the overarching considerations that should be examined by an IRB that wishes to serve as a reviewing IRB?
   The decision whether to serve as a reviewing IRB will require consideration of numerous factors including resources and IRB review capacity as well as systems capacity. The majority of IRB administrative procedures and tracking systems were developed to facilitate the management of an institution’s IRB operations, focusing on the oversight of the institution’s own researchers. While this may include the management of multiple IRB panels, it may not include the capacity to manage multiple research sites and site investigators. The following are some, but not all, of the considerations that may impact a decision whether to serve as a reviewing IRB:
   • the ability to track the status of research at multiple sites;
   • the ability to manage multiple consent forms and versions of consent forms from different sites, including information relating to local context;
   • the ability to communicate notifications of IRB actions to an individual site or across all sites as needed;
   • the ability to store site-specific information (e.g., approval documentation, informed consent documents and other study-specific materials) in a clearly labeled set of IRB materials;
   • the ability to access and apply relevant state and local law;
   • when appropriate, the use of an electronic information system that meets the requirements for Part 11 compliance (if research is FDA regulated) ; and,
   • the ability to monitor and/or audit research at the relying sites
2. What factors should be considered when deciding whether or not to cede IRB review?
   • A key issue is whether ceding review is mandatory or optional. If the use of the single IRB is mandatory for study participation, and the institution wishes not to cede review, the institution would either need to offer a compelling reason why it cannot rely on a single IRB and persuade the sponsor or funder to make an exception, or it would not be able to participate in the study. Some multi-center groups that collaborate on several individual protocols allow for an institution to opt out of single IRB review for individual studies while still remaining part of the parent network and eligible for participation in other studies.
   • The relying institution should consider whether the reviewing IRB has sufficient expertise and experience reviewing and overseeing research of a similar nature to the proposed study.
   • Absent a mandate to rely on a specific IRB, the relying institution should consider the risks to participants in deciding whether to cede review.
   • The relying institution should consider if there are there any features of the protocol or the participant population that pose special concerns and ensure that the reviewing IRB is able to accommodate them. Examples include recruitment from socially or economically disenfranchised populations, local cultural mores or unique clinical circumstances , in which local knowledge might impact the review and approval related to recruitment methods.
   • The relying institution should consider that states may have different record retention and Freedom of Information statutes and judicial precedents that may affect security and accessibility of IRB records.
   • The relying institution should consider if ceding IRB could create or mitigate unique institutional risks such as conflicts of interest.
   • The financial implications of the decision should be determined. This includes an analysis of lost research opportunities (that is, the unwillingness of a sponsor or funder to allow local, non-ceded IRB review) as well as the additional administrative time and costs associated with establishing authorization agreements.
   • The relying institution should consider that from a practical standpoint, investigators, research staff and others will need to learn the electronic systems, policies and processes of the reviewing IRB.
3. How is the decision made as to which IRB will be the reviewing IRB and which institution(s) will be the relying institution(s)?
   There are a number of different ways that the decision as to which entity will be the reviewing IRB and which will be the relying institutions can be made. The sponsor or funder may identify the reviewing IRB; the applicant for funding may propose the reviewing IRB; or the group of researchers involved in the research may collectively decide which IRB they would prefer to serve as the reviewing IRB.
   In all cases, consideration should be given to issues such as expertise in a particular area of research or familiarity with the participant population, or one IRB’s capabilities for serving as the reviewing IRB. SACHRP has previously provided guidance on this topic in its document entitled: “Recommendations on Consideration of Local Context with Respect to Increasing Use of Single IRB Review.”
4. What are the options when two institutions have an existing arrangement where one is the relying institution and one is the reviewing IRB and there is an interest in having a third institution serve as the reviewing IRB for certain studies?
   This can happen for example when Institution A and B have agreed that all of their research be reviewed by Institution B’s IRB (the reviewing IRB) and institution A is the relying institution; but, they wish to rely on a third IRB (C) for one or more specific studies (e.g., at another institution, an independent IRB, the NCI CIRB). There are several options including:
   1. Both (Institution A and Institution B) can sign an authorization agreement directly and independently with Institution C for Institution C’s IRB to serve as the IRB of record for Institutions A, B and C (if C is also conducting the research).
   2. The Institution B could cede IRB review to Institution C. But, he authorization agreement between the Institutions A and B would need to give Institution B the authority to enter into cede review agreement with other IRBs either on a general or case by case basis. Institutions are advised that there may be legal and contractual issues that arise in this situation even though it is acceptable in terms of compliance with the HHS regulations.
5. What is the possible span and extent of an IRB Authorization Agreement?
   Authorization agreements are flexible and can be highly customized. They may cover one protocol, multiple protocols, or all research within a certain set of parameters. The single IRB may negotiate separate agreements with each relying institution or one agreement that all institutions implementing a protocol sign. When an agreement pertains to multiple studies, the scope should be clear including whether the relying institution retains the authority to decline participation in certain studies. For example, an IRB authorization agreement could state that the reviewing IRB will review all research conducted at an institution that has no IRB, or it can limit the research to specific categories (e.g., industry sponsored; oncology only). Alternatively, an IRB authorization agreement may be very specific and cover an individual protocol or a small number of protocols. An IRB authorization agreement could include exclusions for certain types of research. An IRB authorization agreement may include provisions such as the ability of the relying institution(s) to participate in any phase of the IRB review process or obtain information about concerns of other sites.
6. Who is authorized to approve an Authorization Agreement?
   An institutional official or designee must agree with and approve any Authorization Agreement. However, this does not preclude an institution from having policies that require other levels of review and approval prior to final approval by the institutional official.
7. Do changes need to be made to the Federalwide Assurance (FWA) when an institution relies on a different IRB or an IRB serves as the reviewing IRB for another institution?
   Institutions participating in multi-site research do not need to modify their FWA in order to rely on or serve as the reviewing IRB. The FWA form states, “Institutions designating internal IRBs do not need to designate any of the external IRBs upon which it relies.” (FWA Form June 30, 2014) If an institution has no internal IRBs and has designated one external IRB, but decides to rely on a second external IRB that will review the largest percentage of research covered by its FWA, the institution must update its FWA to replace the first external IRB with the second IRB.
   In all cases, reliance on an external IRB must be documented by a written agreement that is available for review by the OHRP upon request.
8. What are the responsibilities of the reviewing IRB and the relying institution(s) with respect to information pertaining to the local context?
   The reviewing IRB must have access to information on local context and must ensure that the review of the research adequately considers local context issues and concerns. Local context generally refers to local circumstances, preferences and variability and could include such issues as variation in language, economic issues, and the like. In general, the relying institution should provide information on local context to the reviewing IRB with updates as appropriate.
9. What are the responsibilities of the reviewing IRB and the relying institution(s) pertaining to applicable state and local laws?
   Both HHS and FDA regulations require that “the IRB shall be able to ascertain the acceptability of proposed research in terms of institutional commitments and regulations, applicable law, and standards of professional conduct and practice.” Information relating to state or local laws that would have implications for the research conducted at the relying institution(s) must be considered by the reviewing IRB. Some states have laws that impact research such as age of majority, additional informed consent requirements, and/or additional privacy notification requirements. The reviewing IRB needs to be aware of the relevant state laws that impact proposed research at participating sites. There are multiple approaches that IRBs can use to facilitate this. A reviewing IRB can develop and maintain a state law database, and put in place mechanisms to identify when research will be conducted in a location with applicable local laws. The reviewing IRB can also obtain the information from the relying institutions.
10. What are some of the key responsibilities of the reviewing IRB and the relying institution(s) with respect to the oversight of research?
    1. Monitoring and Auditing
       The Authorization Agreement should identify what information needs to be relayed to the reviewing IRB relating to its oversight of research. The IRB Authorization Agreement should identify which IRBs/institution will have responsibility for monitoring and auditing or otherwise supervising, as appropriate, the activities at sites relying on a reviewing IRB, including both routine activities as well as for-cause investigations. Relying institutions should consider what role the local research institution will play in review and oversight of a study, given that the local research institution is a site where the research will be conducted and has the best knowledge of (1) the conditions under which the research is implemented and (2) the qualifications of the investigators and study teams. The reviewing IRB may rely on the relying institutions for these functions, but this division of responsibilities should be explicit in the authorization agreement.
    2. Complaints from Research Participants
       The authorization agreement should address the management of participant complaints that includes mechanisms for notifying the relying sites, as well as the reviewing IRB, including institutional officials, of any issues identified at a site. Resolution of complaints will ordinarily require cooperation between the reviewing IRB and the relying institution(s).
    3. Investigator Qualifications and Education
       The IRB Authorization Agreement should specify the process to ensure that investigators participating in the research have adequate qualifications and have undergone required trainingthat this information is communicated to the reviewing IRB.
    4. Responsibility for Conducting Investigations
       The reviewing IRB and the relying institution (s) both have the authority to conduct fact-finding and investigations regarding protocol deviations, noncompliance or unanticipated problems. However, the reviewing IRB will necessarily need to rely on obtaining information from the relying institution, and the relying institution typically will have the greater need and capacity to manage the fact-finding or investigation and greater access to relevant information.
    5. Reporting Responsibilities
       IRBs have a reporting responsibility to organizational officials, regulatory agencies, and sponsors for serious or continuing non-compliance, unanticipated problems involving risks to participants or others, and suspensions or terminations of IRB approval
11. What should the agreement address regarding opportunities for a relying institution to have input into the reviewing IRBs oversight of the research?
    The authorization agreement outlines what type of communication will be established between the relying institution(s) and the reviewing IRB. Productive communication is critical to the success of these arrangements. The reviewing IRB should give the relying institution(s) information about its determinations and access to the minutes so that relying institution(s) may communicate questions or concerns if they so choose. The authorization agreement may also provide relying institutions with access to additional documents. By its nature, single IRB review is based upon confidence in the reviewing IRB to apply the regulations appropriately and protect the participants in the research, but input from relying institutions should not be precluded.
12. How can an IRB authorization agreement arrangement be terminated?
    The IRB authorization agreement should describe the circumstances under which either party could terminate the arrangement. The agreement should be clear regarding each institution’s ability to terminate the relationship and the processes to be followed in the event that IRB oversight must be transferred to another IRB or the study must be closed at the relying institution. Access to records for which the reviewing IRB had responsibility needs to be maintained for the required regulatory period.
13. How should institutional and investigator conflicts of interest be handled when IRB review is ceded outside a relying institution?
    The IRB Authorization Agreement should describe how institutional and investigator conflicts of interest will be managed. If the relying institution is going to manage conflicts of interest, there should be a way for that information to be submitted to the reviewing IRB prior to IRB approval.
14. Who has responsibility for compliance with applicable sections of HIPAA?
    Review and approval of HIPAA authorizations and the waivers of authorization may be conducted by the reviewing IRB. Sites that are covered entities are required to maintain compliance with HIPAA, including all reporting requirements related to breaches. Separate authorizations or separate privacy boards are also acceptable.
15. Who is responsible for conducting IRB review of the grant?
    The Authorization Agreement should state that the reviewing IRB is responsible for assessing consistency between the grant and the protocol.
16. If an institution has agreed to rely on a reviewing IRB for all or a defined portion of protocols, who determines whether an activity is or is not human subjects research requiring review?
    Many institutions have policies that require some level of administrative, regulatory or academic review to determine whether a proposed activity is human subjects’ research that requires IRB review and approval. If the reliance agreement expressly vests this decision-making function in the reviewingIRB, then the relying institution will need to determine administrative mechanisms to refer such questions to the reviewing IRB. It is likely, however, that many institutions may decide to retain this function for themselves, using their existing policies and mechanisms for determining what activities are or are not human subjects’ research requiring review. Thus, a relying institution will need to consider how determinations of what is required to be referred to the reviewing IRB will be made, and whether those determinations should be made by the reviewing IRB or the relying institution.
17. How are the costs associated with ceding IRB review managed by the parties?
    Allocating costs with respect to single IRB review is an evolving issue and involves costs to both the reviewing IRB and the relying institutions. Costs to the reviewing IRB and the relying institution(s) may be addressed separately from the authorization agreement.
18. Are indemnification and liability provisions appropriate in an authorization agreement?
    An Indemnification provision might be requested by either party to an IRB Authorization Agreement but such a request is not required in a reliance agreement. State institutions may not be able to agree to indemnification provisions. All other institutions may find indemnification a matter of negotiation.
    Relying institutions and reviewing IRBs should examine their liability insurance policies to see what the coverage is with respect to insurance that covers the investigators, the institution, as well as the IRB members’ review of research conducted outside of the reviewing IRBs institution, if the reviewing IRB is institutionally based.
19. How does ceding IRB review affect other aspects of the human research protection program?
    The relying institution(s) must consider the impact of ceding IRB review on other functions integral to the safe conduct of research and the protection of human subjects in research. These include, but are not limited to: management of conflict of interest issues and clinical trial agreements, as well as radiation safety and institutional bio-safety review. These reviews may be integrated with the local IRB review and can affect participant safety and IRB review generally. When IRB review is ceded to another IRB, there exists a responsibility to ensure the continued integration of these reviews and communication to the reviewing IRB as necessary and appropriate. It is suggested that relying institutions assess how ceding IRB review will affect existing processes, and what changes are required, in preparation for reliance on a single IRB.
20. What are some examples of standardized IRB authorization agreements that are publicly available?
    • OHRP (http://www.hhs.gov/ohrp/sites/default/files/ohrp/assurances/forms/irbauthorizpdf.pdf)
    • Master Reciprocal IRB Reliance Agreement (https://catalyst.harvard.edu/programs/regulatory/)
    • CTTI (http://www.ctti-clinicaltrials.org/briefing-room/tools)
    • IRB Choice (https://www.irbchoice.org/p/)
    • Smart IRB Reliance Platform (https://smartirb.org/)