Before research on human subjects can begin, federal regulations require independent review and approval by an institutional review board (IRB). An IRB is a committee established to protect the rights, safety and well-being of humans involved in a clinical trial.
The IRB reviews all aspects of the trial, including the adequacy of consent to be obtained from research participants, with the intent to ensure that all human subject research be conducted safely and in accordance with all federal, institutional, and ethical guidelines.
Generally, there are two types of IRBs in the US—local and central. Local IRBs are part of the academic institutions that conduct research, whereas central IRBs are independent entities that can provide review services for studies with multiple research sites. Federal IRB regulations in the US were formulated during the 1970s and early 1980s, when most clinical trials were conducted at a single study site or, at most, a small number of sites. Since that time, there has been significant growth in the volume of research, the number of multicenter trials, and the size and complexity of late-stage clinical trials.
Many researchers have complained that use of different local IRBs to review each research site for a multicenter trial is extremely inefficient and leads to additional cost burdens and trial delays. In a survey conducted by the Federal Demonstration Partnership (FDP) in 2012, principal investigators on federal grants reported that they spend about 42% of their time on "administrative burden", with IRB-related burdens ranking highest. Despite this, many US research sites have been hesitant to use a single, central IRB.
Across the Atlantic, the European Union (EU) has acted (Clinical Trials Directive in 2004) to harmonize reviews of clinical trials by establishing Research Ethics Committees (REC), akin to IRBs, to conduct reviews across member countries for clinical trials, aimed at establishing a more centralized system for review and approval of clinical research. Yet, within EU countries, central, regional, and local RECs often exist, and tensions between these have arisen, including debates on how, and to what degree to unify processes and decisions.
Is there a substantive difference, in terms of efficiency and effectiveness, between reviews conducted by decentralized (local) and centralized IRBs? What are the pros and cons of each? Are local IRBs really even necessary, or do they just create bottlenecks in modern clinical trials?
Problems with Using Local IRBs for Multisite Studies
A 2011 review which evaluated burdens imposed by IRBs on research concluded:
- IRBs operate at different levels of efficiency
- Decisions made (and positions held) by IRBs and their members are not always in accord with regulatory guidance
- Waiting times for approval for the same study protocol are sometimes lengthy and highly varied
- IRBs presented with identical protocols will sometimes ask for different and even competing revisions, and decisions made (and positions held) by IRBs are not always in accord with policy guidance from the Office for Human Research Protections (OHRP)
This review also concluded that, "the interplay of these factors is particularly important to multisite studies in which local IRBs review the same protocol at each participating site. In those instances, the inherent redundancies of duplicative review and the multiplicative consequences of any inconsistent decisions by participating IRBs make it more likely that costs are unnecessarily imposed on research."
In addition to review inconsistencies between different local IRBs slowing down the review process for multisite studies, there are a number of other factors inherent in the structure of local IRBs themselves that can contribute to trial delays and cost increases. Some of these factors include:
- Local IRBs are often composed of volunteers for whom the IRB is one of many responsibilities, so meeting schedules vary dramatically depending on member availability. This leads to local IRBs convening, on average, once or twice a month, at most. A local IRB's infrequent meeting schedule can significantly delay an investigator's study startup.
- Turnover in the staff at local IRBs is often high, and it usually takes a long time to train someone new due to lack of resources. Additionally, at the local level, funds simply aren't available to proactively hire for turnover in the IRB office.
- Local IRBs are no longer attracting prominent academics as they once did. Leading medical school professors may not want to serve on IRBs, because they're too busy running trials, don't want to discipline colleagues, and don't want to spend hours in meetings and reviewing adverse event reports.
- Different IRBs often have different operating procedures, databases, application forms, documentation standards, communication policies.
Local IRBs can't easily transition into a centralized IRB function either. Significant financial and human resources are required to function in the role of a single IRB, and all but the few institutions that have received millions of dollars in special IRB support are ill prepared to function as an effective and efficient central IRB. The people, processes and technology supporting local IRBs were set up to accommodate single site studies only.
The Growing Trend of using Centralized IRBs for Multisite Studies
In recognition of the challenges of using different local IRBs for multisite studies, the FDA released a draft guidance in 2006 to help facilitate use of centralized IRBs for multicenter trials. The guidance explains that FDA regulations allow for review of a study by an IRB at a different location from the actual research site, as long as the central board understands the local context and is sensitive to community values. Recognizing that separate research review at multiple sites can result in "duplication of effort, delays, and increased expenses," the guidance adds that "greater reliance on a centralized IRB review process, in appropriate circumstances, could reduce IRB burdens and delays."
While adoption of centralized IRBs in the US has been more tentative than in the EU, recently, several pharmaceutical companies and contract research organizations (CRO) have begun to require central IRB review as a condition for participating in multi-site studies.
Government-funded US research formally came into alignment with this trend in mid-2016, when the National Institutes of Health (NIH) released its new multisite research policy to streamline IRB review. This policy states, "All sites participating in a multisite study are expected to rely on a single institution review board to carry out functions that are required for institutional compliance with IRB review set forth in HHS regulations at 45 CFR 46" This policy seeks to eliminate numerous IRB reviews for multisite studies that leads to "unnecessary administrative burdens and systemic inefficiencies without diminishing human subjects protections."
A number of other factors contribute to the effectiveness and efficiency of centralized IRBs:
- Central IRBs, which may be commercial for-profit operations or established by public research organizations such as the National Cancer Institute, often have greater resources, access to experts on cutting-edge science, and large information systems.
- Dedicated board members at the central IRB are available to review studies more frequently - once or twice a week, at a minimum. This allows central IRBs to deliver timely review services, while also spending more time thoroughly reviewing each study.
- In comparison to some local IRBs, a central IRB may be better informed of contemporary issues in human subject protections, and thus perform reviews with the most up-to-date information and industry guidance in mind. Smaller institutions can be particularly constrained by limited availability of expertise at the institution, making it more challenging to conduct a thorough, knowledgeable review.
- A central IRB may be more objective in its review than a local IRB, as it is removed from any bureaucracy and institutional politics that might be experienced by a local IRB.
- Centralized review of the consent documents and protocol may free overburdened IRBs and site study personnel to engage in more oversight of local conduct, thereby enhancing protections to research participants.
Barriers to Centralized IRB Adoption
While the trend towards centralized IRBs for multisite studies is increasing in momentum, there are still pockets of resistance. The Clinical Trials Transformation Initiative (CTTI) has identified several barriers to central IRB adoption including:
- A general misunderstanding of the definition, role, and responsibilities of central IRBs
- Lack of experience or familiarity with the process for using a central IRB
- Difficulties with learning how to use of central IRBs
According to CTTI, one of the biggest barriers to using central IRBs is that sites often use local IRBs not only for approving protocols, but also for various site-specific tasks related to clinical trials - training staff, making sure investigators comply with research protocols, and making sure HIPAA privacy rules are being followed. CTTI has issued a number of recommendations to help advance the use of centralized IRBs for multicenter clinical trials. These recommendations include:
- To address blurred distinctions between responsibilities for ethics review and other institutional obligations, CTTI recommends that sites and IRBs use a CTTI-developed guide, also known as the Considerations Document, to support communication and contractual relationships between institutions and a central IRB.
- CTTI recommends that sponsors in a position to require the use of central IRB review for multisite trial networks should do so in order for relevant stakeholders to gain experience with central IRB review. The resulting experiences may foster greater comfort and trust with the central IRB model.
- CTTI recommends use of the CTTI-developed Evaluation Checklists:
- For institutions to determine their readiness to use a Central IRB (federal, academic, or independent IRB) for multicenter clinical trials
- For institutions/sponsors when selecting a particular IRB to serve as the single IRB of record
- For central IRBs when deciding whether to work with a specific institution during a multicenter clinical trial
- To address administrative and legal concerns and to reduce time when first executing a reliance (authorization) agreement, CTTI recommends that institutions and IRBs adopt or begin negotiations with the CTTI-developed IRB authorization agreement template.
- To address local context concerns, CTTI recommends that IRBs and institutions follow the Secretary's Advisory Committee on Human Research Protections (SACHRP): Recommendations on Consideration of Local Context with Respect to Increasing Use of Single IRB Review.
Benefits of Local IRBs
The movement towards use of centralized IRBs for multisite studies has not been without its critics. As expressed by some of these critics, perceived benefits of working with a local IRB include:
- Local knowledge of trial participants: Local reviewers often have more intimate knowledge about the populations the study will target in the local area, potentially providing better protection of the subject's rights and safety. Certainly, centralized IRB members can make a point to connect with those in the local community that can provide this information, however.
- Local knowledge of Principal Investigators (PI): A local IRB knows investigators, and it knows the facilities. It understands the capacity and capabilities of researchers, and can appreciate whether a particular protocol is a reasonable undertaking. However, personally knowing a PI can also create problems, since local politics, or personal bias, may cause IRB officials to feel direct or indirect pressure to approve a study.
- More interactions between reviewers and PI facilitate better study protocols: PIs may interact more fully and informally, and hence in many ways more effectively, with local rather than centralized IRBs. Informal conversations can help shape studies early on, clarifying what research approaches may be ethically problematic before they are more elaborately pursued.
- Added incentive to adequately protect subjects: As many local IRB members are clinicians at the institution, they may feel a higher level of responsibility and moral obligation to their patients. This may cause them to put more effort into the review and thus do a better job. Still, centralized IRB members can also share this sense of moral duty.
While the benefits of moving towards centralized IRBs for multisite studies are clear, there is simply not enough data as of yet to warrant the complete replacement of local IRBs. Clearly, there is some benefit to having local representation in the review of clinical studies - enhanced local knowledge of subject populations and PIs (e.g., awareness that certain populations are vulnerable, or that a certain PI has been somewhat careless in the past) is useful, as it can facilitate human subject protection by raising caution in reviewing certain protocols.
The debate must therefore evolve beyond a simple dichotomous discussion of whether centralized IRBs should replace local IRBs, and into an examination of different hybrid models and what the relative advantages and disadvantages of each are. Policy makers and others need to carefully consider the difficult tradeoffs that emerge in the local IRB vs. centralized IRB discussion, and focus on developing a system that provides the efficiency and effectiveness of centralized IRBs, without losing the benefits that local IRBs provide. The shift towards centralized IRBs will likely continue, but we need to make sure that something critical is not lost in the process.
Multi-tiered models like those that have been instituted in the EU may be of assistance here. Such a system might still include some local review (e.g., allowing local reviewers to contribute to central IRB discussions), but in a way that does not facilitate increased expenses, time delays, and discrepancies. We need a nuanced analysis of how these and other models may best serve the ongoing efforts to better protect the rights and safety of human subjects in clinical trials, while also facilitating an effective and efficient system that speeds the delivery of life-saving drugs to market.
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President and Founder
Jae Chung is the president and founding visionary of goBalto. A startup evangelist, Chung wants to change the way pharma and CRO companies initiate clinical trials. goBalto's purpose-built study startup SaaS solution allows stakeholders to better adhere to established timelines and budgets, with customers reporting reduction in cycle times by 30-plus percentage, thereby getting medicines to those in need faster.
Chung works with Rock Health to mentor healthcare technology startups, and previously co-founded Celltrion (068270:KOSDAQ), a leading biopharmaceutical manufacturing company. Prior to Celltrion, he worked as a strategy consultant with McKinsey & Company.
In 2013 Jae was recognized as a FierceBiotechIT Top-10 Techie list and in 2010 was awarded the Bio-IT World Judges Prize for Technology Innovation. Jae has experience in drug development, commercialization, and business development. He has an MBA from New York University and holds a CPA.
Article originally published in Insite (Spring Edition of the SCRS Magazine), March 2017