The National Institutes of Health issued a draft policy on December 3, 2014 promoting the use of a single Institutional Review Board Review. The draft guidance would mandate the use of a single IRB in any NIH-funded/supported multi-site study for sites located within a U.S. jurisdiction. The proposal assumes the mandatory use of single IRBs will increase efficiency of IRB review, prevent duplication of effort, and prevent disparities among protocols and informed consent forms in multi-site studies that often have reviews by multiple local IRBs.
The draft policy proposes limited exceptions to use of a single IRB. Exceptions would only be permitted if: (1) the designated single IRB is unable to meet the needs of specific populations; or (2) where local IRB review is required by federal, tribal or state laws or regulations.
Improving the efficiency of the system for the review, approval and oversight of research involving human subjects is a laudable goal. Efficiency issues in the pre-approval review process likely include much more than just the IRB process. There are many research focused committees, departments and offices that play a role in the pre-approval review of human subjects’ research. These include, but are not limited to radiation safety, pathology, pharmacy, nursing, institutional bio-safety, billing, grants and contracts. Mandating single IRB review for domestic multi-site studies is not the appropriate solution to improve turn-around time for human subject’s research.
While the use of single IRBs may be effective and efficient in some circumstances, SACHRP believes that it is premature at this time to mandate single IRB use in NIH funded domestic multi-center trials. Requiring a single IRB to review a multi-site research protocol may well, as described below, result in new procedures and policies being created by the relying institutions (those institutions relying on another institution to conduct the IRB review) and the reviewing institution (the institution responsible for serving as the single IRB of record) that will undermine the goals of this policy change and create a host of new challenges for research institutions.
Summary of Recommendations
SACHRP recommends that:
- NIH fund research evaluating the advantages and disadvantages of single IRB use in domestic IRB multi-site research;
- NIH collect and disseminate data regarding its own experience with the use of single IRBs for grants that have been mandated to use a single IRB (e.g., the NeuroNEXT multicenter trial) or for those grants where it was voluntarily utilized;
- NIH support meetings with the research community where issues regarding the use of a single IRB can be discussed in a public forum;
- NIH evaluate the cost issues and provide a proposal that would cover the cost of both single IRB review and local review without reducing dollars to the researcher;
- Until data is available, rather than mandating review by a single IRB, NIH find mechanisms to encourage investigators and institutions to voluntarily utilize single IRBs as part of their grant submissions. This could be accomplished by providing incentives such as additional dollars to those grants that agree to utilize single IRB arrangements.
Need for More Data
More data should be developed and provided to the research community prior to imposing such a requirement on U.S. research efforts. Notably, the policy only identifies one paper dating back to 2010 in support of the statement that single IRB use in multi-site studies is more cost effective[1], and that paper concerns a national central IRB, not the ceding of review by multiple institutions to another institution’s IRB. Comprehensive data is needed to assess: (1) the advantages and disadvantage of single IRB review on the reviewing IRB; (2) the advantages and disadvantages of single IRB review on the relying institution; (3) the categories of research that are most appropriate for single IRB review; (4) the impact on local review concerns; and (5) the cost of a single IRB system on the various institutions.
In general, SACHRP supports the voluntary increased use of a single IRB for multi-site studies, where appropriate, as such use may, in some circumstances, decrease differences, some of which may be arbitrary and some of which may be principled, among site implementation of protocols. Data might show that this could bring about a more rapid and efficient IRB review and continuing review processes; could increase predictability for researchers, all of whom would be operating under the same approved protocol and consent documents; and could make IRB review of unanticipated problems in the course of a study more meaningful and accurate, thus potentially better protecting the welfare of subjects.
We recommend a careful and well thought-out evaluation of what has been frequently discussed as the potential benefits of a single IRB review. The NIH draft policy focuses on “efficiency” as a key reason for requiring and justifying mandatory single IRB review. However, substantial experience suggests that the IRB review contributes only modest if any to the delays between project inception and subject recruitment. Further, improved efficiency from the perspective of the study sponsor and/or investigators may entail substantial changes in institutional policies, procedures, and tools, such as software platforms. Incremental gains in one domain may create substantial costs in others.
Evaluation of Impact on Relying and Reviewing Institutions
Mandatory single IRB review could serve to create increased burdens on all institutions. Most institutions have systems that are not necessarily designed for the purpose of managing multi-site research and thus service as a central IRB would require substantial resources, increased cost and re-tooling of processes for the site that serves as the IRB of record.
A significant barrier to institutional adoption of a single IRB for multi-site research is the information technology required to ensure adequate review, communication, and oversight. Systems currently serving IRBs and institutional human research protection programs differ from one another, are complex and expensive, and are not interoperable. Institutions incur significant expense to build technical solutions customized and appropriate to the needs of their institution. Changing existing technology to incorporate communication and management of research being conducted at numerous outside sites is a considerable obstacle that has to be acknowledged and addressed.
The reviewing site will need systems to ensure on-going communication with the other sites, as well as a system for managing and tracking agreements and protocol related issues. The relying sites will have to create other processes to manage reviews that are frequently linked to the local IRB review such as management of HIPAA requirements, radiation safety, as well as budgeting among other such internal committees and departments. Investigator conflicts of interest and institutional conflicts of interest are two significant reviews that are often tied to the IRB review because conflicts of interest may well result in IRB determinations regarding: (1) additional information that should be included in the consent; (2) additional monitoring by an independent DMC or DSMB; or (3) removal of an individual as the primary investigator of a research study.
Consideration of local and regional variations in some circumstances and for some studies will be critical to assuring the welfare of subjects in research. In addition to widely different subject populations, other factors with significant variations among sites would include:
- State laws governing human subjects and/ research data (e.g., genetic testing, genetic privacy, health information laws that go beyond HIPAA, mental health information, mental retardation and developmental disabilities information, surrogate consent, inclusion of children in research, age of majority, age of consent to certain medical treatment such as for substance abuse, investigator licensing requirements, etc.);
- “Emergency research” undertaken without subject consent, for which the FDA requires local community consultation;
- Disparate cultural norms among populations targeted for recruitment;
- Varying investigator and research team experience, which may require more or less oversight during the conduct of the research; and,
- Varying institutional policies regarding availability of compensation for subject injury.
Qualifications of the Reviewing IRB
The method of selection of a single IRB in a specific study is critical; the IRB selected should have the appropriate expertise for the research being reviewed, and the capacity to act as coordinator, receiver and dispenser of critical study-related data to the sites, their research teams, their IRBs and their institutions.
Consideration also should be given to a process for qualifying a single IRB. SACHRP has identified the following issues as points to consider for IRBs serving in a central capacity. These are only some of the numerous issues that need to be addressed:
- Adequate record keeping systems and written standard operating procedures for tracking each site independently, including the ability to manage site-specific emergency care, conflicts of interest, sub-studies, unique consent forms, subject complaints, compliance issues, and unanticipated problems;
- Process to adequately obtain knowledge of state laws where the single IRB reviews sites in other states in order to assure compliance;
- Written SOPs describing how local cultural and resource context information will be gathered, both at initial and continuing review;
- Capacity to conduct site visits, as necessary;
- Written SOPs describing how the single IRB and institutions will coordinate issues such as review by other committees (IBC, Radiation, etc.,) and unique institutional policies;
- Accreditation of its human research protection program; and
- Appropriate oversight by OHRP and FDA.
Evaluation of Costs of Single IRB Review
Costs of review and legal responsibilities for monitoring research and assuring its appropriate conduct would need to be allocated among a central IRB, local sites, their local IRBs, or other designated study reviewers. A cost allocation cannot be a categorical decision to fund a single IRB but not provide resources for the local reviews.
Finally costs to support the single IRB review and the local relying institutions should not be dollars that will reduce the amount of money that would otherwise be available to conduct the research. Budgets for grants should increase where single IRB review is an integral part of the proposal and take into consideration the additional costs to both the reviewing and relying institutions.
Importance of Consistent and Uniform Reliance Agreements
Any discussion of use of a single IRB would have to include consideration of the mechanics of implementing such processes for the reviewing IRBs and the relying institutions as well as the cost incurred by both. Reliance arrangements require complex coordination and communication to manage such issues as how the single IRB would interact on an ongoing basis with local IRBs or designated ethics reviewers in regard to, for example, the emergence of risks that might be unique to a site, the local investigator or its study population, and the implementation of uniform or site-specific measures to mitigate those risks. Single IRBs in multi-site studies should be expected, as part of their initial review and approval, to establish formal written standard operating procedures for accomplishing this in an ongoing way during the course of the approved studies. Yet this may be so complicated that without careful planning and implementation, such a system coupling local review with a single IRB would, in the end, be less efficient than the current practice of each IRB performing its own separate review.
A significant challenge to single IRB systems is the development and management of inter-institutional agreements and processes. Whether single IRB review is mandated or voluntary, tools need to be provided to the research community to ensure consistent and reasonable approaches. NIH needs to evaluate and work with institutions and the larger research community to fully develop a single IRB review model that addresses the issues faced by all of the involved parties. Central IRBs are operating now in many NIH-funded and industry-sponsored studies. They can provide the data on which evaluations can be made as to issues arising regarding legal responsibility, IRB and institutional liabilities, as well as general advantages and disadvantages of such systems. Institutions that defer to one another in a central IRB process need inter-institutional agreements, by which central IRBs and institutions engaged in research can more specifically describe what each party would do in a functioning central IRB model. Without more specific guidance on these points, it would likely not be possible for the entire research community to establish template inter-institutional agreements, while issuance of such specific guidance likely would ease and speed the emergence of templates.
Evaluation of Data on Prior Experiences
Given the various complexities discussed above, it is not surprising that adopting a central IRB model, when tried, has presented some tough challenges. Anecdotally SAHRP understands that the VA has experienced difficulties in implementing a single IRB system. For example, it has been difficult to develop information technology systems across sites to track studies and study reporting, and to coordinate communication among investigators, local facilities, and the VA Central IRB members and staff. Other challenges include considering and accommodating unique local conditions and affiliation arrangements, establishing methods for collecting, analyzing and then reporting back to local sites regarding unanticipated problems, and coordinating study monitoring that is necessarily done by the VA facility sites. If these issues have occurred within the VA system, then one would expect the problems to be more serious, complex, and acute if a mandate for single IRBs for all domestic multi-site studies were simply imposed by regulation or policy.
The NCI CIRB model has itself caused delays in the review process when investigators are asked repeatedly to re-format documents; fix hyperlinks; change margins; and, institutions are not advised of how to integrate reviews such as radiation safety reviews that have a direct impact on the language contained in the research informed consent document.
SACHRP strongly maintains at this time that a uniform mandate of single IRB review for all domestic multi-site studies is premature. SACHRP instead takes the position that a more measured and careful process of encouraging single IRB use, accompanied in a step-wise way by issuing guidance on critical issues involved in the use of single IRB review, would result in less disruption of the research enterprise and eventual improvements in a single IRB process that is anchored in deep collective experience.
[1] Wagner, TH, et al, Costs and Benefits of the National Cancer Institute Central Institutional Review Board J. Clin Oncol 2010; 28:662-666.
