The wait is over. For the past few years researchers and their respective research institutions have faced the distinct probability that the regulations to protect individuals who agree to volunteer in a research study will be significantly changed. After much discussion on proposed changes to the Common Rule in the Notice of Proposed Rulemaking (NPRM), the Department of Health and Human Services (HHS) is poised to publish a Final Rule. “We expect to publish the Final Rule before the end of the year,” according to an HHS spokesperson.
A taste of what the changes will entail was published in the Federal Register in mid-June in the form of the new NIH policy, Final NIH Policy on the Use of a Single Institutional Review Board for Multi-Site Research.1 The NIH policy is a clear window into what IRBs and other research professionals should expect as the federal government prepares to make significant changes in the Common Rule. There are two significant differences between the new NIH policy and the NPRM. First, it is a policy, not a regulation. Second, the NIH policy makes reliance on a single institutional review board (sIRB, how the government delineates this new term) as a term and condition of NIH funding for a research study.
The goals of both the NIH policy and the NPRM proposal are the same — to eliminate duplicative IRB review, reduce administrative burden, and improve human research protections. The NIH policy on the use of sIRB for multisite research is similar to one of eight new regulations proposed in the NPRM. The policy applies to domestic sites of NIH-funded multisite studies in which each site conducts the same protocol involving non-exempt human research, whether it is supported through grants, cooperative agreements, contracts, or the NIH Intramural Research Program. It does not apply to career development, research training, or fellowship awards, according to the Federal Register notice. “Applicants/offerors will be expected to include a plan for the use of an sIRB in the applications/proposals they submit to the NIH.” The policy also applies to the NIH Intramural Research Program.
The NPRM proposed changes pertaining to required use of a sIRB expand the scope of the NIH policy and, as a federal law, have enforcement power. The NPRM lists the following as one of the changes: Mandate that U.S. institutions engaged in cooperative research rely on a single IRB for that portion of the research that takes place within the United States, with certain exceptions. 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.2
The NPRM would apply to multisite research covered by the Common Rule for federally funded research AND clinical trials conducted by a site that receives federal funding for ANY research, unless the trial is subject to FDA regulations, says Emily Chi Fogler, counsel in the Academic and Clinical Research Group within the Health Care Group at Verrill Dana LLP, Boston. Chi Fogler says that the NPRM and the NIH policy “foreshadow a shift to a regulatory and funding landscape requiring sIRB review of multi-site research.” During a Public Responsibility in Research Medicine and Research (PRIM&R) webinar on July 12, she advised participants on strategies for navigating common areas of uncertainty in the NIH policy and for addressing key implementation challenges outlined below.
Tracy Ziolek, executive director for human research protections at the University of Pennsylvania (also a presenter at the PRIM&R webinar) expects a major shift for IRBs. “There will be a paradigm shift in IRB review,” says Ziolek, who directs Penn’s IRB that includes nine IRBs. Ziolek says the new requirements have created a number of challenges including the need for a broader financial structure to cover costs and a specific plan for communication among all parties.
The effective date of the NIH policy is May 25, 2017. Research institutions need to be prepared for the first of many changes coming next year and the next few years as phase-in occurs. FDA is expected to issue its own changes that are harmonized to the Common Rule.
The federal government promulgated the current federal law (regulations) on the protection of human subjects in research in 1981. 21 CFR Part 50 pertains to FDA regulations, and 45 CFR 46 pertains to U.S. Public Health Service regulations. Both are titled “Protection of Human Subjects.” 21 CFR 56 was also enacted in 1981 and is called “Institutional Review Boards.”
At that time, the vast majority of research studies were conducted at academic medical centers (e.g., Harvard University School of Medicine, The George Washington University Medical Center). Under the new federal law, institutions that applied for and received federal funding to conduct research at their institution had to assure the government that research study participants would be protected against the appalling practices such as the U.S Public Health Service Syphilis study in Tuskegee, Alabama, just 12 years earlier.
Given that the new federal regulations required a review board to be established to review proposed research protocols and monitor the study, it is logical that the term “institutional review board” was born. 45 CFR 46.102 (b) defines an “institution” as “any public or private entity or agency, including federal, state, and other agencies.” It goes on to say in 45 CFR 46.102 (g), “IRB means an institutional review board, established in accord with and for the purposes expressed in this policy.” Also, in 45 CFR 46.102 (h), “IRB approval means the determination of the IRB that the research has been reviewed and may be conducted at an institution within the constraints set forth by the IRB, and by other institutional and federal requirements.”
“No law or national directive defines an IRB or requires research to be reviewed in a uniform way, regardless of researcher affiliation or funding source,” say Robert Amdur and Elizabeth Bankert in their 2002 textbook, Institutional Review Board: Management and Function.3 “In situations where research is subject to federal regulation, the definition of the IRB and the procedures for research review are described in detail in the Code of Federal Regulations.”
When research is not subject to federal regulation, the general consensus among research sites has been that the ethical aspects of a research study should be addressed by a system that models the federal IRB system, say Amdur and Bankert.
Regulation 45CFR 46.107 outlines IRB membership requirements in specific detail:
An IRB may, in its discretion, invite individuals with competence in special areas to assist in the review of issues, which require expertise beyond or in addition to that available on the IRB. These individuals may not vote with the IRB.
Ironically, nothing in the federal regulations requires the IRB to actually be at the institution where the study will be done and where it will draw its membership. Now, 35 years after development and implementation of this system for human research protections, the question is not whether the original one IRB for one research study for one research institution is meeting today’s needs.
“The research enterprise has evolved so that IRBs are now affiliated with community hospitals, associations providing funding for research, and regulatory agencies, says Felix Khin Maung Gyi, co-founder of Chesapeake Research Review Incorporated in Columbia, Maryland, one of the first non-institutional IRBs in the United States. Gyi, who started his career in the academic/institutional IRB world, discussed the pros and cons of each model in this article in the American Medical Association Journal of Ethics.4 As Gyi notes, “Central or independent IRBs are not affiliated with any researcher or research institute. All types must comply with the same regulations governing the protection of research subjects.”
“Central and independent IRBs came into existence because researchers who had gravitated away from the academic medical centers and toward the community and private practice maintained their research interests. These investigators primarily conducted pharmaceutical, device, and biologics company-sponsored research but did not have access to an IRB. The independent IRBs fulfilled that requirement, enabling researchers outside the academic medical systems to conduct research in compliance with federal regulations,” says Gyi. The NIH policy and NPRM requirement of sIRB use in multi-site trials is the next evolution.
Meeting challenges of single IRB requirement
Over the past three decades, the number of independent IRBs has grown exponentially. The number of multisite research trials also has increased dramatically. In the last 5-10 years, there has been an expansion of reliance arrangements, including broader scope of protocols and greater number and geographical diversity of sites, says Ziolek. “The NIH policy and proposed Common Rule mandate for single IRBs further expand reliance and bring new requirements and challenges,” she says. Now, and in the near future, Ziolek says research institutions will find themselves in many new relationships, including large scale, multi-protocol, “master” agreements. Participants may be very geographically diverse, include sites of different types (public/private, institutions/MD groups/health centers, large/small), as well as independent sIRBs. There will be shifts in roles and alternatively one or more IRBs will rely on another IRB or provide the IRB review (reciprocal agreements).
A number of U.S. research institutions already have collaborated on reliance and/reciprocal agreements in this new paradigm, says Ziolek. Penn had decided to take on the responsibility of being a sIRB. Sites seeking NIH research funding in the first half of 2017 and beyond will have to decide whether it is best for their institution to become either the reviewing institution or the relying institutional. “Most research sites do not have the capability to serve a much larger need for review and oversight,” says Michele Russell Einhorn. Independent IRBs that have been reviewing protocols for some multisite trials will be asked to take on more, but they too need to step up their level of expertise and development of new technology to meet the data requirements, says Einhorn. She recently left Dana Farber Cancer Institute in Boston as the senior director of the Office of Human Research Studies to assume a new role as the Vice President of Oncology Services at Schulman and Associates in Cincinnati. This long-standing independent IRB expects to increase its available services to include oncology expertise by creating the new position and recruiting her to accept the task. Schulman & Associates has been named as the national IRB for Cancer Moonshot 2020.5
In December 2014, NIH released the draft of the new single IRB policy. It collected feedback for two months and evaluated common themes and concerrns. Chi Folger says the results were that 70% of those who commented on the proposed changes were in favor, with still numerous comments on how to improve or adjust the policy. Chi Folger’s practice focuses on a range of issues and areas related to the conduct and oversight of clinical research, including human subjects protection, HIPAA privacy, and other regulatory compliance including single, central, and other cooperative IRB review arrangements.
Chi Fogler describes the new NIH policy as follows: “Study teams must include their plan for a single IRB review at the time of application (including communication plans, identification of the IRB of record, and confirmation from all sites that they will comply with the NIH policy on sIRB review.) If awarded, NIH approval of the proposal for single IRB use will appear as a term and condition in the Notice of Award or Contract Award letter. A site will be able to get an exception only if either the IRB of record policy is prohibited by local law or if there is a particularly compelling reason, she advises. Exceptions need to be submitted for NIH review.”
Communication is critical
Ziolek outlined an 11-point communication plan that suggests best practices now used at the University of Pennsylvania. It recommends the following timeline:
There must be ongoing communication after the IAA, says Ziolek. For all facets and sites of the study, the IRB of record should submit and organize all unanticipated events and non-compliance, and conduct/facilitate monitoring at other sites as necessary. The relying IRB should provide the IRB with local context, report changes or unanticipated events to the local IRB, and provide data safety monitoring reports.
With the use of a single IRB, the study team and/or the principal investigator may have additional responsibilities because the IRB is serving a new role. For example, a member of the study team or central principal investigator could be the liaison between the relying IRB and the IRB, since most submission systems do not allow outside submitters. Other added responsibilities include having someone assigned to uphold and execute all procedures in the study as outlined in the protocol. Likewise, someone must report all anticipated events and noncompliance to the IRB of record and/or to the sponsor as agreed upon in the IAA.
In addition, Penn has approved a more in-depth progress report at continuing review that allows the research team to clearly describe and answer for themselves the study progress at the local and macroscopic levels. This allows the team to “get a report from relying sites to better assess progress and hear how they think the study is going,” says Ziolek.
Definitions, roles, and responsibilities
Under the new NIH policy, the Final Rule defines the agreement that documents respective authorities, roles and responsibilities, and communication between an institution/organization providing the ethical review and a participating site relying on the sIRB as an Authorization Agreement or Reliance Agreement. “A multisite study uses the same protocol to conduct non-exempt human subjects research at more than one site. The participating site in a multisite study is a domestic entity that will rely on the sIRB to carry out the site’s initial and continuing IRB review of human subjects research for the multisite study. The sIRB is the single IRB of record that has been selected to carry out the IRB review requirements at 45 CFR part 46 for participating sites of the multisite study.”
In the application for funding, the applicant is expected to submit a plan that describes the use of an sIRB that will be selected to serve as the IRB of record for all studies. The plan should include a statement confirming that participating sites will adhere to the sIRB policy and describe how communications between sites and the sIRB will be handled. The applicant may request direct cost funding for additional costs associated with the establishment and review of the multi-site study by the sIRB, with appropriate justification.
The sIRB is responsible for conducting the ethical review of the NIH-funded multisite studies for participating sites. The sIRB may also serve as a privacy board if applicable to fulfill HIPAA requirements. All participating (or relying) sites are expected to rely on an sIRB to carry out the functions that are required for institutional compliance with IRBs set forth in regulations.
A core responsibility for all sites is the investigating and reporting of events, says Chi Fogler. “The potential challenges to an sIRB system are a lack of familiarity with other participants, different definitions or standards for what is an unanticipated problem or serious or continuing non-compliance.” She notes there may be different expectations for timing and the mechanism for reports, and geographical distance may pose a barrier to on-site investigation. She also recommends the following:
When is external reporting to OHRP required? Whose federalwide assurance (FWA) applies? Chi Fogler advises that the relying site’s FWA determines the reporting obligation to OHRP for the relying site. The reviewing site cannot override this determination. Who makes the report? It may track with the nature of the event and who conducted the investigation, she says. Options are to decide who reports as a mutual case-by-case decision or to set the default but allow for mutually agreed case-specific override.
NIH promises to issue guidance materials before the effective date of the new policy (see above) and to post them on this website: http://osp.od.nih.gov/office-
Regulations governing human subject research in the United States are about to change drastically. As research practitioners, including investigators, study staff, IRB members, and others, await the Final Rule on changes that will be made to the Common Rule, they need to prepare for these changes. The NIH Policy on Use of a Single Institutional; Review Board for Multi-site Research published in June 2016 can be an impetus for all researchers to start developing plans. According to Ziolek, the following steps must be done prior to the effective date (May 25, 2017):
“Keep calm,” Ziolek says.”The new landscape necessitates flexibility, balancing of multiple competing/different interests, and open communication among reviewing/relying parties, and with investigators.”
By Terry Hartnett
This article was reprinted from Research Practitioner, Volume 17, Number 5, September-October 2016.