CENTRAL and SINGLE Irbs HAVE ARRIVED: IS COUNSEL READY?
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CENTRAL AND SINGLE IRBs HAVE ARRIVED: IS COUNSEL READY?
NACUA 2016 CLE WORKSHOP November 16-18, 2016
Heidi Gertner Karin Mullin Melissa Havens Hogan Lovells The Forsyth Institute WIRB-Copernicus Group Washington, DC Cambridge, Massachusetts Princeton, NJ
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I. Introduction
The Institutional Review Board (IRB) is integral to ensure protection for human research participants in the United States. And recently, the government has taken several steps forward to shape the IRB landscape, in an effort to streamline and expedite the review process of clinical trials and medical treatment innovation. One of these steps is mandating the use of a single IRB, also sometimes called a central IRB, for certain multi-site research studies occurring in the United States (U.S.). This single IRB model takes away the option for a clinical trial protocol to be reviewed and approved by the IRBs of each participating site, and allocates responsibility for the oversight of a clinical trial at all participating sites to just one single IRB. With this change, many issues need to be considered by counsel representing academic institutions that conduct clinical trials funded by the U.S. Department of Health and Human Services’ (HHS) National Institutes of Health (NIH). This paper will discuss these issues and offer considerations going forward. Following an initial bird’s eye view of the regulatory developments relating to the single IRB, the paper will explore (a) the allocation of responsibilities between a single IRB and the institution participating in the trial, (b) issues for academic institutions to consider in selecting a single IRB, and (c) IRB reliance agreements.
II. How Did We Get Here? NIH’s New Single IRB Policy and Regulatory Developments
a. A Brief Background on IRBs
On July 12, 1974, in response to public outcries concerning abuses in a study involving African-American men suffering from syphilis (colloquially called the Tuskegee study), Congress passed the National Research Act,1 which established the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (the Commission). On April 18, 1979, the Commission issued the Belmont Report, which lay the foundation for ethical
1 Pub. L. 93-348, 88 Stat. 342 (1974).
1 \\DC - 704955/000300 - 9094707 v2 principles applicable to clinical research in the United States.2 The three main principles focused on 1) respect for persons 2) beneficence and 3) justice.3 Based on the Commission's work, HHS expanded its regulations for human subject projection and required entities under its jurisdiction that receive federal funds for research involving human subjects to have the research reviewed by an IRB.4 On June 18, 1991, fourteen other agencies followed suit, and adopted the same set of regulations, in what is now called the “Common Rule.”5 That day, the Food and Drug Administration (FDA) also issued its own final rule6 to amend its regulations to substantially conform to the Common Rule. More specifically, the regulations mandate that an IRB must review all research that is conducted, supported, or regulated by HHS, FDA, or one of the other federal agencies that promulgated the Common Rule.7 The IRB’s primary responsibility is to ensure that human subjects’ rights and welfare are protected.8 To achieve this, for each proposed clinical trial, the IRB reviews details such as the study’s objectives, procedures, and eligibility requirements for participants.
b. S hift Toward Single IRBs
Currently, and until NIH’s single IRB policy becomes effective in March 2017 (which will be explained further below), institutions involved in multi-site research are permitted, but not required, to use joint review by a single IRB.9 Industry sponsors of multi-site research have encouraged or required single review for over 20 years. Though not a mandate, the agencies, like industry, have long recognized the benefits of a single IRB process. In the preamble to
2 The Belmont Report, available at: http://www.hhs.gov/ohrp/regulations-and-policy/belmont- report/. 3 Id. 4 45 CFR Part 46. 5 56 FR 28003 (June 18, 1991). See also Office for Human Research Protection, OHRP 45 CFR part 46 Frequently Asked Questions (FAQs), available at: http://www.hhs.gov/ohrp/regulations-and-policy/guidance/faq/45-cfr-46/index.html. 6 56 FR 28025 (June 18, 1991). 7 21 CFR 56.101(a), 56.103(a); 45 CFR 46.101(a), 46.109(a). 8 21 CFR 56.102(g). 9 See 21 CFR 56.114 (“In complying with these [Part 56 Institutional Review Boards] regulations, institutions involved in multi-institutional studies may use joint review, reliance upon the review of another qualified IRB, or similar arrangements aimed at avoidance of duplication of effort.”); 45 CFR 46.114 (“Cooperative research projects are those projects covered by this policy which 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. With the approval of the department or agency head, an institution participating in a cooperative project may enter into a joint review agreement, rely upon the review of another qualified IRB or make similar arrangements for avoiding duplication of effort.”); see also FDA, Cooperative Research – Information Sheet, available at: http://www.fda.gov/RegulatoryInformation/Guidances/ucm126422.htm.
\\DC - 704955/000300 - 9094707 v2 HHS’s 1979 proposed regulations protecting human subjects, the predecessor to the current Common Rule, HHS viewed single IRBs as a way to “reduce duplicative review of multi- institutional studies.”10 Fast forward to March 2006, when FDA issued a guidance entitled “Using a Centralized IRB Review Process in Multicenter Clinical Trials,” (FDA’s Centralized IRB Guidance). 11 There, FDA also encouraged the use of single IRB (in this case, calling it a central IRB).12 In the guidance, the agency stated that it “hopes sponsors, institutions, [IRBs], and clinical investigators involved in multicenter clinical research will consider the use of a single central IRB (centralized IRB process) especially if using centralized review could improve the efficacy of IRB review.”13 The guidance recommends relying on a single IRB to evade inefficiencies: such multiple reviews by multiple IRBs can result in unnecessary duplication of effort, delays, and increased expenses in the conduct of multicenter clinical trials. Greater reliance on a centralized IRB review process, in appropriate circumstances, could reduce IRB burdens and delays in the conduct of multicenter trials.”14 Subsequently, on April 30, 2010, HHS’ Office for Human Research Protections (OHRP), which provides clarification and guidance and maintains regulatory oversight over IRB programs in connection with the Common Rule,15 published a “Letter on Use of a Centralized IRB.”16 In the letter, OHRP stated that it “fully agrees with FDA’s position on the benefits of relying on a single central IRB for multicenter research,” referring specifically to FDA’s Central IRB Guidance.17
10 44 FR 47699, 47700 (Aug. 14, 1979). 11 FDA Guidance for Industry, Using a Centralized IRB Review Process in Multicenter Clinical Trials, available at: http://www.fda.gov/downloads/RegulatoryInformation/Guidances/ucm127013.pdf. 12 Id. 13 Id. at 7 (PDF Page 10). 14 Id. at 2 (PDF Page 5). 15 See About OHRP, available at: http://www.hhs.gov/ohrp/about-ohrp/index.html. 16 Letter from Jerry Menikoff, Director, Office for Human Research Protections, to James T. McDeavitt, Senior Vice President, Carolinas Medical Center, Office of Human Research Protection (April 30, 2010), available at: http://www.hhs.gov/ohrp/regulations-and- policy/guidance/april-30-2010-letter-to-dr-james-mcdeavitt/index.html. 17 Id. The letter was in response to Carolina HealthCare System’s letter, which was seeking clarification on OHRP’s view regarding external IRBs and issues of liability between central and local IRBs. See Letter from James. T. McDeavitt, Senior Vice President, Carolinas Medical Center, Office of Human Research Protection to Jeffy Menikoff, Director, Office of Human Research Protections, (April 13, 2010), available at: http://www.hhs.gov/ohrp/regulations-and- policy/guidance/april-13-2010-letter-to-dr-james-mcdeavitt/index.html.
3 \\DC - 704955/000300 - 9094707 v2 c. HHS’s ANPRM and NPRM on the Common Rule
On July 26, 2011, HHS issued an Advanced Notice of Proposed Rulemaking (ANPRM) which would significantly revise the Common Rule.18 Among other things, it would require the use of one IRB of record for multi-site studies, subject to certain exceptions, and requested comments on this proposal.19 Almost four years following the ANPRM, on September 8, 2015, HHS and fifteen other federal agencies issued a Notice of Proposed Rulemaking (NPRM) to revise the Common Rule.20 They followed through with the ANPRM’s proposal to mandate that all sites in a multi-site study rely on the approval of a single IRB.21 The proposal generally applies to all multi-site research subject to the Common Rule that is conducted in the U.S., with two exceptions.22 One exception would be for research that requires additional (i.e., local) IRB review pursuant to other laws.23 The second exception would be for federally funded, supported, or conducted research, where the federal agency determines that use of a single IRB is not appropriate for the study. 24 The NPRM notes that the proposal would not prevent an institution from conducting its own additional IRB review of a project, but the local IRB’s review would not be binding on its institution under the regulations, and OHRP would not enforce its terms. 25 Nonetheless, sites would not be relieved of their other obligations under the regulations to protect human subjects.26 Further, for research funded by a federal agency, the agency would select the reviewing IRB. 27 For research not funded by a federal agency, the lead institution conducting the study would select the reviewing IRB. 28 Interestingly, the agency made clear that for research where local viewpoints are significant, however, e.g., recruiting vulnerable populations, local IRB review could be used, but noted that it is not the only way to address these issues.29 The NPRM reiterated that the following does not warrant local IRB review: the adequacy of the informed consent form/process and the evaluation of a study’s social value, scientific validity, risks, and benefits. 30 The NPRM also stated that the institution and the IRB should establish and follow written procedures identifying the compliance responsibilities of each entity, and that the procedures and
18 76 FR 44512 (July 26, 2011). 19 Id. at 44522 (July 26, 2011). 20 80 FR 53933 (Sept. 8, 2015). 21 Id. at 54027 (§ _____.114) (Sept. 8, 2015). 22 Id. 23 Id. 24 Id. 25 80 FR 53993, 53984 (Sept. 8, 2015). 26 Id. 27 Id. 28 Id. 29 Id. 30 Id.
\\DC - 704955/000300 - 9094707 v2 responsibilities should be specified in an agreement between the institution and IRB.31 Institutions would have three years from the final rule’s publication to comply.32
d. Final NIH Policy on the Use of a Single Institutional Review Board for Multi- Site Research
Another arm within HHS, NIH, also continued the push toward single IRBs in the same time period. On December 3, 2014, the NIH issued for comment a draft “NIH Policy on the Use of Single Institutional Review Board (IRB) for Multi-Site Research.”33 In the draft policy, NIH stated that it “generally expects all domestic sites of multi-site NIH funded studies to use a single IRB of record.” 34 On June 21, 2016, NIH issued the final policy and set forth the requirement that a single IRB of record be used in the ethical review of non-exempt human subjects research protocols funded by NIH that are carried out at more than one site in the U.S.35 More specifically, the policy applies where each site serves the same role in the same protocol, whether supported through grants, cooperative agreements, contracts, or the NIH Intramural Research program. 36 The NIH clarified that it will grant exceptions if review by the proposed single IRB would be prohibited by federal, tribal, or state law, regulation, or policy and would consider a request for exception on other grounds if there is a compelling justification.37 In light of this change, the policy explains each party’s responsibilities in the research process. The applicant/offeror must submit a plan to NIH that identifies the use of a single IRB that will serve as the IRB of record for all sites.38 According to the policy, the plan should provide details such as how the single IRB will be used, and how communications between sites and the single IRB will be handled.39 If a single IRB has not been identified in delayed-onset research, the policy permits the application/proposal to include a statement that the awardee will follow the policy and communicate plans to use a registered IRB of record to the funding NIH Institute/Center prior to initiating the study.40 In either circumstance, NIH specifies that the applicant/offeror is responsible for assuring that the single IRB is qualified to serve, as the plan
31 Id. 32 80 FR 53933 (Sept. 8, 2015). 33 Policy on the Use of Single Institutional Review Board (IRB) for Multi-Site Research (Dec. 14, 2014), available at: http://grants.nih.gov/grants/guide/notice-files/NOT-OD-15-026.html. 34 Id. 35 See Notice Number: NOT-OD-16-94, Final NIH Policy on the Use of a Single Institutional Review Board for Multi-Site Research, at 1, available at: http://grants.nih.gov/grants/guide/notice-files/NOT-OD-16-094.html; see also 84 FR 40325 (June 21, 2016). 36 Id. at 8-9. 37 Id. at 11. 38 Id. at 8-9. 39 Id. at 10. 40 Id.
5 \\DC - 704955/000300 - 9094707 v2 will not be evaluated in peer review.41 NIH also states that the applicant/offeror may request direct cost funding for the single IRB’s additional costs, with appropriate justification.42 If the NIH accepts the plan, it will be incorporated as a term and condition in the Notice of Award or in the Contract Award.43 The awardee will then have certain important responsibilities, though it may delegate the tasks associated with these responsibilities.44 Its responsibilities include ensuring that the authorization agreement, also called the reliance agreement, is in place and maintained.45 This agreement is to document the roles and responsibilities between the institution/organization providing the ethical review and a participating site relying on it. 46 The awardee must also ensure that a mechanism for communication between the single IRB and participating sites is established. As discussed above, the single IRB is the IRB of record and is responsible for conducting the ethical review for participating sites.47 The policy explains that the single IRB must carry out the regulatory requirements under the HHS regulations48 and stated that it may function as a Privacy Board to fulfill the requirements of the HIPAA Privacy Rule.49 The single IRB should also work with the awardee to facilitate communication between it and the participating sites.50 Although all sites will rely on the single IRB in part, they are nonetheless responsible for meeting other regulatory obligations. 51 These include obtaining informed consent, managing the approved protocol’s implementation, and reporting unanticipated problems and study progress to the single IRB. 52 Participating sites must also share information needed for the single IRB to consider state/local regulatory requirements and local context issues.53 Interestingly, the policy does not prevent sites from doing their own “ethical review,” although it notes that it would be against the policy’s intent, and NIH will not pay for it.54 The policy applies to: 1) all competing grant applications (new, renewal, revision, or submission) with receipt dates on or after May 25, 2017; 2) all solicitations for contracts issued on or after May 25, 2017; and 3) intramural multi-site studies submitted for initial review after
41 Id. at 8. 42 Id. at 10. 43 Id. 44 Id. 45 Id. 46 Id. 47 Id. 48 45 CFR Part 46. See Notice Number: NOT-OD-16-94, Final NIH Policy on the Use of a Single Institutional Review Board for Multi-Site Research, at 10. 49 See Notice Number: NOT-OD-16-94, Final NIH Policy on the Use of a Single Institutional Review Board for Multi-Site Research, at 10. 50 Id. 51 Id. at 10-11. 52 Id. 53 Id. at 11. 54 Id.
\\DC - 704955/000300 - 9094707 v2 May 25, 2017.55 Ongoing, non-competing awards are not expected to comply with the policy until the grantee submits a competing renewal application. 56
III. Division of Responsibilities Between Single IRB and Institution
A common and highly relevant issue raised by counsel for academic institutions when considering the use of single IRBs has been the allocation of responsibilities. This is particularly important when such responsibilities require coordination or involvement by both the institution and the IRB and/or the institution has assigned non-IRB functions to the IRB. The preamble to HHS’s NPRM addresses the need for formal documentation of such allocation, and specifically states: “written procedures identifying the compliance responsibilities of each entity . . . should be set forth in an agreement between the institution and the IRB specifying the responsibilities of each entity.”57 One model available is the Authorization Agreement and Division of Responsibilities between the National Cancer Institute (NCI) Central Institutional Review Board and the Signatory Institution.58 Other models include the HHS OHRP’s “Institutional Review Board (IRB) Authorization Agreement”59 and Clinical Trials Transformation Initiative’s “Template IRB Authorization Agreement.”60 In addition to these models, single IRBs may have their own form agreements that suit the manner in which their IRB services are provided.
a. Ancillary Reviews
Ancillary reviews may be mandated by law, institution policy and/or other obligation. An institution’s internal IRB may be responsible for carrying out its regulatory-mandated IRB duties as well as other related institutional duties that are specific to that institution but may not be at a single IRB. As a starting point for determining whether ancillary reviews are appropriate to reference in a contract with a single IRB, the single IRB and institution may be best served to consider the scope of the IRB’s review to be limited to those reviews required by regulation. With respect to review of research staff conflicts of interest, IRBs accredited by the Association for the Accreditation of Human Research Protection Programs (AAHRPP) are required to make the final conflict of interest analysis. In these cases – provided the institution does not simply rely on the IRB’s conflict of interest process – the institution and single IRB will work together
55 Id. 56 Id. 57 80 FR 53933, 53984 (Sept. 8, 2015). 58 Authorization Agreement and Division of Responsibilities between the NCI Central Institutional Review Board and the Signatory Institution available at: https://ncicirb.org/cirb/documents/AA_DofR.doc. 59 HHS, Institutional Review Board (IRB) Authorization Agreement, available at: http://www.hhs.gov/ohrp/register-irbs-and-obtain-fwas/forms/irb-authorization- agreement/index.html. 60 Clinical Trials Transformation Initiative, Project, Central IRBS, available at: https://www.ctti-clinicaltrials.org/projects/central-irbs.
7 \\DC - 704955/000300 - 9094707 v2 to determine the manner in which each respective party’s conflict of interest analyses, management plans, and conflict-of-interest-related consent language are reconciled.
b. Subject Injury Compensation
The content of some sections in a consent form, such as compensation for research related injury, may be influenced or dictated by institutional policy and/or the clinical trial agreement entered between the sponsor and institution. The institution should alert the single IRB to any such terms and the parties should work together to develop an efficient mechanism to include text in the IRB-approved informed consent form that is acceptable to the IRB and the institution.
c. Regulatory Reporting
Both HHS and FDA regulations require the IRB to maintain written procedures on ensuring prompt reporting to the IRB, institutional officials, and the department or agency supporting/conducting the research (or FDA) of any “unanticipated problems involving risks to subjects or others,” any serious or continuing noncompliance with the regulations or IRB requirements/determinations, or any suspension or termination of IRB approval.61 It is the responsibility of the investigator to report to the IRB matters that the IRB may consider it to be an unanticipated problem or instance of non-compliance. The IRB’s policies and federal guidance on such should be carefully followed. Each institution covered by an OHRP-approved assurance must have procedures in place to report to the supporting HHS agency head any unanticipated problems or serious or continuing noncompliance findings made by the IRB, and any suspensions or terminations of IRB approval.62 It is a joint responsibility of the institution and IRB to determine how it will report such findings. In some cases an institution may wish to report these findings directly, but in other cases the institution may rely on the IRB to submit such reports. Whatever the parties decide, it is advisable to assign this responsibility to one party in the IRB reliance agreement.
IV. Some Issues to Consider in Selecting a Single IRB
Although a single IRB can be an efficient way to obtain initial review and lead to faster enrollment and conclusion of trials, it may present difficulties that need to be considered when, for example, drafting and negotiating IRB reliance agreements. Below are some common challenges that should be considered.
a. Differences between Institution, Single IRB, and Participating Sites Policies
61 45 CFR 46.103(b)(5); 21 CFR 56.108(b). 62 45 CFR 46.103(a); OHRP Guidance, Unanticipated Problems Involving Risks & Adverse Events Guidance (2007) available at: http://www.hhs.gov/ohrp/regulations-and- policy/guidance/reviewing-unanticipated-problems/.
\\DC - 704955/000300 - 9094707 v2 An institution, single IRB, and the participating sites may have different policies that will need to be aligned. For instance, each of these parties may have different reporting deadlines for noncompliance, “unanticipated problems involving risks to subjects or others”63, and continuing review. This necessitates that each party conducts a close review of the other parties’ policies to determine any relevant differences, and potentially account for those differences in an agreement or otherwise. It is important to note, however, that single IRBs maintain their own policies, as required by regulation,64 and are accordingly constrained to following these.
b. Local Considerations
b.i. Local Committee Scientific Expertise Required
Additional local review may be required by other regulations and/or committees, such as a Radioactive Drug Research Committee (RDRC) in the case of radioactive drugs for research.65 This committee must be approved by FDA and composed of individuals with specific expertise, such as a physician recognized as a specialist in nuclear medicine, a person qualified by training and experience to formulate radioactive drugs, and a person with special competence in radiation safety and radiation dosimetry.66 The committee must either be associated with 1) a committee established by a state authority to provide advice on radiation health matters or 2) a medical institution operated for care of patients and with the scientific expertise to allow for selection of committee members from its faculty.67 Another example of a committee that may need to review the protocol other than the single IRB would be an institutional biosafety committee (IBC), if the research involves recombinant or synthetic nucleic molecules, although independent IRB review can be coupled with an IBC managed by the same entity.68 These reviews often would be analyzed locally and could be reflected in the IRB reliance agreement accordingly, although this is not necessarily required or even appropriate, as such reviews are distinct and separate from the IRB review and/or matters of local policy.
b.ii. HIPAA and Privacy Considerations
63 45 CFR 46.103(b)(5); HHS Guidance on Reviewing and Reporting Unanticipated Problems Involving Risks to Subjects or Others and Adverse Events (January 2007), available at: http://www.hhs.gov/ohrp/sites/default/files/ohrp/policy/advevntguid.pdf. 64 45 CFR 46.115(a)(6) 65 21 CFR 361.1(b)(1). 66 Id. at 361.1(c)(1). 67 Id. 68 NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules (April 2016), at PDF Page 15 available at: http://osp.od.nih.gov/sites/default/files/resources/NIH_Guidelines.pdf.
9 \\DC - 704955/000300 - 9094707 v2 FDA and HHS both require that IRBs confirm that the research it approves provides for adequate protection of the privacy of subjects and the confidentiality of data.69 Local review may be assumed to be preferable because, for example, privacy statutes and regulations vary by state. Single IRBs do, however, address compliance with local privacy laws, as well as the privacy and confidentiality regulatory requirement, in a variety of acceptable ways. The institution will be best served by evaluating how a single IRB complies with this regulation to determine whether a single IRB’s review of privacy and confidentiality measures are acceptable. One way of conducting such an evaluation is to request information about the specific procedures the single IRB follows to review privacy and confidentiality issues. NIH explicitly states that a single IRB can serve as a HIPAA Privacy Board and review HIPAA issues,70 but under the IRB regulations the IRB has no obligation to do so. Determining whether the single IRB will fulfill this responsibility is important to clarify early and prior to submission of a clinical trial protocol to that IRB. As most institutions include HIPAA authorization in the study consent form (vs. a standalone HIPAA authorization form), it is common for IRBs to serve as HIPAA Privacy Boards.
b.iii. Other Local Laws and Regulations
An IRB needs to be cognizant of local and state research-related laws and regulations, as some may occasionally be more restrictive than federal regulations. Normally it makes sense that a single IRB would allocate responsibility to a local attorney for review of the local and state laws and regulations because of their local expertise. For instance, state laws governing genetic testing and informed consent requirements vary, and often require local interpretation. Further, even if OHRP holds the single IRB responsible for identifying and applying state laws in reviewing and determining the approvability of a project, state and local enforcement authorities may well focus on the institution that is subject to those laws. The institution’s risks usually cannot be removed or contracted away by HHS or FDA. Thus, institutions will want to take an active role in the review of local laws and regulations in collaboration with the single IRB. It should be noted that these issues apply to multi-site industry-sponsored clinical research as well, and have been adequately addressed by numerous hospitals over the last 20 years.
b.iv. Other Ancillary Responsibilities
Institutions frequently intermix IRB duties with other institutional duties. Consequently, it may be operationally difficult for an institution to extract the responsibilities of the IRB from the other institutional duties. NIH noted that some commenters to the draft NIH policy expressed concern that a single IRB would disturb the “checks and balances” at institutions. An IRB’s additional responsibilities may relate to compliance with institutional policies (e.g., reviews for conflict of interest, scientific merit of the study, and investigator qualifications)
69 21 CFR 56.111(a)(7) ; 42 CFR 46.111(a)(7). 70 Notice Number: NOT-OD-16-94, Final NIH Policy on the Use of a Single Institutional Review Board for Multi-Site Research.
\\DC - 704955/000300 - 9094707 v2 which are intertwined with the research oversight responsibilities.71 To help resolve this issue, the IRB reliance agreement could contemplate which entity(ies) will conduct these ancillary reviews and any other issue not strictly “ethical” or required by IRB regulation or guidance to be reviewed solely by the single IRB. Some reviews will not be able to be delegated to the single IRB. For instance, the local IRB/participating site normally would perform its own investigator conflict of interest analysis under its relevant policies, and submit this as part of the information provided to the single IRB. However, if it is determined that the single IRB is to review for such issues, or it does so as a matter of course or as required by an accreditation standard for example, the IRB reliance agreement could require the sites to provide certain categories of information to the IRB in order to facilitate the review, and the timeframes for providing such information.
b.v. Other Special Local Context Issues
FDA and HHS regulations further require that IRBs be qualified through experience, expertise, and diversity of members, e.g., considering race, gender, cultural backgrounds, and sensitivity to community attitudes to promote respect for its advice in protecting human subjects’ rights and welfare.72 FDA and HHS also require that the IRB is able to ensure that selection of subjects is equitable, meaning that the IRB can consider the setting in which the research will be conducted and is aware of the special problems of research involving vulnerable populations.73 Other issues that require local expertise are local standards of care, the availability of emergency support for high risk protocols, level of diagnostic testing available (if applicable), the type of oversight supported, the potential subject population’s economic status and educational level, and drug or device formulary issues. If the single IRB is not also a local IRB, institutions using that IRB are advised to become familiar with the manner in which the single IRB works with the institution and makes itself aware and informed of any such information. Subject recruitment issues require an in-depth knowledge of the patients in individual communities, as community attitudes about the nature of the proposed research, ethical standards of the local community, and mechanisms of minimizing risks to vulnerable populations, are all implicated. Whether these issues should be allocated for review to a local IRB and if not, how a single IRB may become familiar with such issues, depends on the facts of each study. In some scenarios, it might be safest to build into the IRB reliance agreement a local IRB’s review of such local issues.74 In other scenarios this information can be provided by the institution to the IRB following such IRB’s standard research review submission forms and processes. In evaluating single IRBs, institutions should consider whether such IRBs implement safeguards to ensure they consider local context in a manner acceptable to the institution and, as applicable, in
71 Id. at 3. 72 21 CFR 56.107(a); 45 CFR 46.107(a). 73 21 CFR 56.111(a)(3); 45 CFR 46.11(a)(3). 74 FDA Guidance for Industry, Using a Centralized IRB Review Process in Multicenter Clinical Trials, at 5 (PDF Page 8).
11 \\DC - 704955/000300 - 9094707 v2 accordance with FDA guidance.75 Single IRBs will likely maintain IRB policies and research submission requirements apart from the agreement that requires the submitting site to provide the IRB with relevant local context information. Institutions relying on a single IRB are advised to: 1) become familiar with the manner in which the single IRB ensures that it is aware and remains informed of all such information, and 2) confirm the adequacy of the single IRBs processes before deciding to rely on that IRB. This confirmation may be handled through verbal conversations and/or documented in the form of an IRB policy, IRB submission form, investigator handbook, FAQs, or some other document.
c. Communications and the Close Relationship between the Sites and Single IRB
Communications between the single IRB and the relying sites is extremely important, as it fosters regulatory compliance (e.g., timely submission of continuing review reports), timely completion of IRB reviews (e.g., notification of missing or incomplete review materials), staying current on local research context developments, closer relationships, and trust. In communication matters, local IRBs are sometimes considered to have an advantage over the single IRB, as local IRB staff may offer more timely and convenient assistance due to close physical proximity, as opposed to a single IRB, which may be in a different time zone. Consideration should, however, be given to the communication model, hours of availability, level of staffing, level of expertise of the single IRB staff, and support services established by the single IRB, specifically for its relying non-local sites, as these may provide a superior alternative to the local IRB. It should also be noted that regardless of whether a single IRB or local IRB is utilized, strong and open communication between the sites, designated institutional contacts, sponsor/ contract research organization (CRO) as applicable, and the IRB is essential. One may view local IRBs as more advantageous to single IRBs because they possess internal knowledge about their sites and investigators. In evaluating a single IRB, the institution should determine if and how the IRB accounts for such internal knowledge, which may include the investigator’s experience with conducting clinical trials, whether there is research staff supporting the investigator, the ratio of research staff to research subjects and trials, access to emergency medical care (as applicable), licensure and regulatory compliance history of the research personnel, and the research personnel’s completion of human subject protection training. Information such as this should be the type of knowledge shared at the outset of the institution-IRB relationship. Important information that arises locally over the course of the relationship should be shared promptly with the single IRB if such knowledge impacts human research protections. Both parties should commit to close and prompt communication for the duration of their relationship.
75 21 CFR 56.107(a); FDA Guidance for Industry, Using a Centralized IRB Review Process in Multicenter Clinical Trials. The OHRP Guidance on local context, “IRB Knowledge of Local Research Context,” has been archived as “its content is no longer applicable under Federal Wide Assurances approved by OHRP,” available at: http://wayback.archive- it.org/4657/20150930182921/http://www.hhs.gov/ohrp/archive/policy/irb_knowledge- local_rsrch_context.pdf.
\\DC - 704955/000300 - 9094707 v2 An increased level of transparency and accessibility will lend to increased trust between the single IRB and the relying sites, and the ability to strengthen their relationship. Therefore, the IRB reliance agreement could include specific mechanisms to facilitate communication between the two (e.g., set times for daily or weekly open office hours if the site has questions, a dedicated point of contact for the relying institution, a periodic status meeting) and require that documents reflecting the single IRB’s deliberations, e.g., meeting minutes, be available for the participating sites.
V. IRB Reliance Agreements
An IRB reliance agreement between institution(s) and the single IRB can take many forms. The terms in such an agreement may be required by regulation or guidance, or be legally prudent, but many are optional. There is no agency mandate as to the specific form the agreement must take. The directive OHRP provides to institutions that rely on an IRB operated by another institution or organization is that the institution must “ensure that this arrangement is documented by a written agreement between the [Federal-wide Assurance (FWA)-holding] Institution and the other institution or organization operating the IRB that outlines their relationship and includes a commitment that the IRB will adhere to the requirements of the Institution’s FWA.”76 Further, the agreement must be kept on file at both the FWA-holding institution and the IRB. OHRP provides a sample institutional authorization agreement, or “reliance agreement,” for use by institutions with an FWA when that institution wishes to rely on the IRB of another institution.77 This agreement is brief – and aside from identification of the parties and studies subject to the agreement – it includes five sentences of substantive terms. For limited or short term engagements with an external IRB, such as ones involving review of one or only a few studies from time to time, this type of agreement may be most suitable. For long term relationships, a full services contract with all normal contractual provisions is typically preferable. This would generally include identification of the parties, description of the IRB services to be performed, description of the studies the IRB will review, responsibilities of the IRB, responsibilities of the institution, responsibilities that can go to either the IRB or the institution, confidentiality, term and termination, compensation, access to the IRB’s records, recordkeeping, regulatory inspections, indemnification, limitation of liability, insurance and the standard miscellaneous terms such as governing law and notices. For more complex engagements, such as large health care systems, universities with multiple campuses or institutions involved with consortia, a full and more detailed contract reflecting the relationship amongst the institutional parties as well as the reviewing IRB(s) is often necessary and desirable. One way this can be structured is for the parent or lead institution to enter master terms with the
76 HHS Federalwide Assurance (FWA) for the Protection of Human Subjects, available at: http://www.hhs.gov/ohrp/register-irbs-and-obtain-fwas/fwas/fwa-protection-of-human- subjecct/index.html. 77 HHS Sample Institutional Review Board (IRB) Authorization Agreement, available at: http://www.hhs.gov/ohrp/sites/default/files/ohrp/assurances/forms/irbauthorizpdf.pdf.
13 \\DC - 704955/000300 - 9094707 v2 IRB(s) and then have each individual campus or facility wishing to enter the agreement and utilize the IRB to join by way of a joinder negotiated by that parent/lead institution. One consideration is the level of detail to be included in the IRB reliance agreement. In sections addressing operational details (e.g., the IRB’s research submission requirements, institution-required consent form text, the institution’s human research protection program staff who are to receive a copy of the IRB’s formal communications to investigators, the party responsible for making payment for services to the IRB), it is important to bear in mind that the terms should be specific enough to adequately address each party’s responsibilities. However, the terms should also be general enough to recognize that policies, preferences, staff, etc. will change over time and that the parties will likely prefer flexibility in how the finer details of the relationship are handled. Further, it is often desirable from the IRB’s perspective to include a statement affirming that nothing in the agreement is to be construed to limit the independent role the IRB is charged with playing under the IRB regulations. Likewise, it may be important to articulate that nothing in the agreement is to be construed as altering the IRB’s primary responsibility to research subjects and the protection of their rights and welfare. Last, some relying institutions may wish to expressly require the IRB to maintain good standing with OHRP, FDA, NIH, other relevant agencies or accreditation bodies, and further require the IRB to provide notice in the event the IRB falls out of good standing with any of these parties.
a. Regulatory Liability for the IRB Review
The HHS IRB regulations hold the institution responsible for human research protections regardless of the IRB overseeing the research.78 However, the 2015 HHS NPRM proposes changing this regulation:
To encourage the use of IRBs that are otherwise not affiliated with or operated by an assurance holding institution (“unaffiliated IRBs”), this NPRM also includes a proposal that would hold such IRBs directly responsible for compliance with the Common Rule.79
Under FDA’s IRB regulations, the reviewing IRB has direct responsibility for compliance with the regulatory requirements.80 FDA has the authority to conduct audits and inspections of IRBs reviewing FDA-regulated research and to take direct enforcement actions against the IRB, including disqualification of an IRB.
b. Commonly Negotiated Terms in IRB Reliance Agreements
78 45 CFR 46.103(a). 79 80 FR 53937 (Sept. 8, 2015). 80 21 CFR Part 56.
\\DC - 704955/000300 - 9094707 v2 The most commonly negotiated terms in an IRB reliance agreement include:
a.i.1. IRB’s compliance with an institution’s policies (e.g., codes of conduct, travel expenses, confidentiality); a.i.2. The party responsible for sending regulation-required notices to FDA and OHRP for reportable findings such as serious and continuing non-compliance; a.i.3. Notification regarding regulatory audits conducted at the IRB (pertaining to the IRB’s compliance with the IRB regulations or the institution’s studies); a.i.4. Institutions’ request for the IRB to enter a HIPAA Business Associate Agreement; a.i.5. Indemnification and Limitation of Liability (which are commonly tied to sovereign immunity or other limitations on liability that state entities may enjoy under state law or constitution); a.i.6. Insurance (professional liability); a.i.7. Compensation, to include the party to be invoiced and notification of changes to fees; and a.i.8. Recordkeeping, including return of records.
VI. Conclusion
Adoption of the single IRB model may be challenging for academic institutions that prefer and/or are accustomed to their local IRB model. Yet with the issuance of the final NIH single IRB policy and anticipated Common Rule developments, it is prudent for all academic institutions engaged in NIH funded clinical trials to initiate efforts to determine how they can implement the single IRB model. Policies and practices for working within the single IRB model should be developed in order to work efficiently with single IRBs and avoid hampering the human subject protections and conduct of clinical trials at the institution.
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