Clinical Researcher—April 2018 (Volume 32, Issue 4)
Pranali M. Wandile, MS, CCRP
U.S. Food and Drug Administration (FDA) guidance documents, particularly the cooperative research guidance given in 21 CFR 56.114 of the Code of Federal Regulations, only provide suggestions and recommendations. These recommendations do not have legal force. Still, the FDA urges sponsors, institutions, institutional review boards (IRBs), and clinical investigators involved in multicenter clinical research to adhere to these guidelines and requirements as outlined in 21 CFR part 56.
These guidelines recommend the use of a centralized IRB review process in situations where doing so could improve the efficiency the review. In multicenter trials, however, review by both central and institutional IRBs can duplicate efforts, increase expenditures, delay clinical trials, and cause confusion and miscommunication. Meanwhile, undergoing only a centralized IRB review and foregoing the institutional IRB review can save time, reduce expenditures, reduce delays in subject enrollment, and decrease the workload and financial burden on an institution.
This article stresses that protecting the rights, safety, and welfare of study subjects is the most important element of clinical research, and that researchers can meet all of these goals by using either a central IRB or an institutional IRB, instead of using both.
Observations from the Field
Taking part in the challenging development of a clinical research department in a brand new institution where the staff were unfamiliar with the fundamentals of clinical trials, the author found that administrators at the new facility wanted their studies to be review by a local IRB, but at the time, they only had an incomplete IRB standard application. We found critical pieces of information regarding the operation of institutional IRBs were missing, such as the requirements for establishing an IRB infrastructure, IRB functions, initiation of the IRB review process, etc. Nor were the administrators aware of the option for using a centralized IRB review process.
Looking at the hospital infrastructure and the resources our site had, we thought the centralized IRB review process would be the most suitable option for clinical trial oversight at our facility. After all, quality conduct of clinical trials is of utmost importance, and trials should not proceed without thorough IRB review.
We e-mailed the FDA questions regarding IRB determination for our new research site, and we were pleased to receive a prompt response to our questions. After conversations with the FDA, we were able to answer the new facility’s most puzzling questions. This experience prompted the development of this article to share the “lessons learned” from this experience.
The FDA’s guidance regarding the use of centralized IRB review processes in multicenter clinical trials assists sponsors, institutions, IRBs, and clinical investigators in meeting the requirements of 21 CFR part 56. While these requirements have no legal force, the recommendations do provide standards to which facilities should try to adhere.1
The guidelines allow facilities to use only the centralized IRB review process, especially when this centralized review could improve the efficiency of the IRB review. Multiple offices within the FDA established these guidelines, including the Center for Drug Evaluation and Research (CDER), the Center for Biologics Evaluation and Research (CBER), the clinical practice program in the Office of the Commissioner, and the Office of Regulatory Affairs.2
21 CFR part 56 addresses the IRB review and approval process. These guidelines apply to clinical investigations that are subject to Investigational New Drug (IND) regulations, unless they are exempt from IRB requirements under part 56.104.
Responding to a history of significant abuses human study subjects have endured in various notable experiments, regulators developed procedures intended to ensure the safety of participants. These abuses led to the creation of the National Research Act of 1974 and the Belmont Report, which required researchers who use human subjects to adhere to critical ethical principles. The ethical principles include respect for persons, beneficence, and justice. An IRB may approve human research only in situations in which a) the potential benefits to society outweigh the risks to subjects, b) there is unbiased selection of study subjects, and c) equal distribution of risks and benefits to eligible participants is present.3
Principle Investigator and IRB Review Responsibility
The principal investigator (PI) bears ultimate responsibility for the complete oversight of the study, and for assuring compliance with IRB policies and procedures along with the locally applicable regulations and guidelines from competent authorities.
For studies conducted under the aforementioned IND application with the FDA, the sponsor of the IND must obtain assurance that the PI will meet the requirements outlined in 21 CFR part 56 pertaining to the IRB review and approval processes. In fact, sponsors initiate the process by submitting site information to the IRB, or by instructing the site to submit study and site information to a central IRB (the IRB suggested by sponsor) for review and approval.
In a multicenter trial, if the PI is conducting clinical research in an institution with its own local IRB, then he or she must follow the policies of that institution. However, the institutional policies can also state that the PI pursue review through a centralized IRB or through the institution’s IRB, or through joint review responsibilities of both.2
The Requirements for IRB Membership
As per 21 CFR 56.107(a), an IRB member must have sufficient experience, expertise, and diversity to ensure adherence to the IRB’s advice and counsel in safeguarding the rights and welfare of human subjects.
Usually, sponsors utilize a central IRB to oversee a study. If an institution has its own IRB, then depending on the institutional policies, the institution may need to submit the study to its own IRB for study approval and oversight, it may opt to partially depend on a central IRB, or it may make the central IRB fully responsible for study oversight.2
Centralized IRB Review of Research Protocol
In multicenter trial cases of institutions that have their own institutional IRB nevertheless wishing to rely on a central IRB for partial or complete review of the study, the institutional IRB should sign an agreement with the central IRB. Copies of that agreement should be held by the institution, the investigator, and the central IRB.4 There should be written procedures for both IRBs that address these questions:2
- How does the institution’s IRB determine that the central IRB is qualified to review research conducted at the institution?
- How does the central IRB intend to communicate with investigators, relevant institutions, and with the institution’s IRB regarding its review?
- How does the central IRB ensure that it provides meaningful consideration of relevant local factors for communities from which research subjects will be enlisted for the study?
- How does each IRB share responsibilities under the agreement?
- How does the central IRB measure the ability of a remote site to participate in a study (e.g., to make sure the site has medical services appropriate to the complexity of the study)?
- How does the central IRB perform initial and continuing review responsibilities at remote sites?2
In the case of the study being launched by the research-naïve institution mentioned earlier, the author and others at the institution found the experience of using only a central IRB was extremely positive. Staff were able to start the study within two months of the day the sponsor approached the institution with the new study proposal. While the contract department reviewed the contract and budget, a research coordinator submitted the study to the central IRB. By the time the contract and budget negotiations were finalized, the IRB had approved the research protocol.
In short, using the central IRB saved a remarkable amount of time, resources, and expenditures from the study start-up phase until its closure—time that was capitalized on by staff to focus on quality study conduct and oversight.
Benefits of Using a Central IRB
In a multicenter clinical trial, it can become a very costly and time-consuming scenario if each institution involved submits the research protocol to its own IRB as per the institutional IRB guidelines, possibly leading to major delays in the initiation of the study activities at all of the study sites. Generally, institutions have multiple studies going on at the same time, and using both an institutional IRB and a central IRB in every case unnecessarily duplicates efforts, increases expenditures, and delays clinical trial conduct.5–7
Utilizing the centralized IRB review process for multicenter trials can save time and expenditures, reduce further delays in enrollment, and reduce the workload of the institutional IRB. Thus, many institutions use their own local IRB specifically for internally funded, investigator-initiated clinical trials, but opt for central IRB services for externally funded clinical trials.
The FDA’s “Guidance for Industry Using a Centralized IRB Review Process in Multicenter Clinical Trials” mentions that the use of a centralized IRB review process is consistent with the requirements of existing IRB regulations. CFR 56.114 on Cooperative Research states that “institutions involved in multi-institutional studies may use joint review, or rely upon the review of another qualified IRB, or similar arrangements aimed at avoidance of duplication of effort.”8
In fact, a central IRB can be created for reviews of multicenter trials in specific therapeutic categories by members who are highly qualified in their medical specialties. For example, the National Cancer Institute (NCI) has a central IRB that reviews all NCI-sponsored adult oncology Phase III multicenter trials. Study sites conducting NCI trials can use the NCI’s central IRB, or they can use their own IRB for study oversight.1
Some multicenter trials involve multiple academic medical centers. In such cases, each single medical center can use its own IRB, or can accept study oversight from another participating medical center’s IRB. These two medical centers can sign the cooperative agreement accordingly.
One of the biggest advantages of using a uniform central IRB in a global multicenter trial is that the central IRB collects the clinical trial information from all of the active sites across the globe. If the central IRB review and oversight is efficient, then it will be able to detect safety problems quickly and easily, which will not only be helpful in further continuing the trial, but for all future pipeline studies for the same investigational product.
Issues with Utilizing a Central IRB
The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research suggested that IRB members should include “men and women of diverse backgrounds with sufficient maturity, experience, and competence, so that the IRB will be able to do its responsibilities, and its determinations will be accorded respect by investigators and the community served by the institution or in which it is located.”9 It is also suggested that the IRB members be able to determine whether the proposed research is acceptable in terms of standards of professional conduct and practice, institutional commitments, regulations, and applicable laws.
A central IRB can be located within an institution that is conducting a multi-institutional research study, and can provide oversight for different sponsors and across study sites not located in the same territory in which the IRB and its host institution are based. In such cases, the central IRB may not be fully knowledgeable about the details “on the ground” at the various sites. For example, site management organizations or hospitals may use a central IRB that is not located in the community in which an actual study is being conducted.
However, the central IRB still needs to review a variety of factors with an unbiased approach, including the attitudes of the communities where the research is being conducted, the ethical standards found locally,10 and any pertinent local cultural influences on the population from which research subjects will be enrolled. Even members of a very experienced central IRB may not be aware of these nuances in all of a study’s settings.
Therefore, a centralized IRB review process should include the following provisions to ensure that these relevant local factors receive substantial consideration:
- Individuals or organizations familiar with the local community of a study site should submit relevant local information to the central IRB.
- The centralized IRB’s limited review of the study should be followed by the relevant institutional IRB’s limited review of the same study, focused on the issues of concern to the local community.2
According to 21 CFR 56.114, for the centralized IRB review process, “Institutions involved in multi-institutional studies may use joint review, or [may] rely upon review of another qualified IRB, or similar arrangements aimed at avoidance of duplication of effort.”
In the case of a joint review, confusion and miscommunication can occur, as not all of the study staff will be aware of the details of a local IRB’s agreement with a central IRB. In such cases, knowledge must be thoroughly disseminated to the study staff so that both IRBs can efficiently oversee the clinical trial.
Local IRB Review of Research Protocol
IRB regulations require that the IRB should be able to ascertain the acceptability of proposed research in terms of institutional commitments, regulations, applicable laws, standards, or professional conduct and practice. These requirements are applicable to both local and central IRBs.
IRB review through members who have been carefully selected (based on their subject matter expertise and/or familiarity with the local community) is intended to provide meaningful consideration of a variety of factors in assessing research activities. These factors include unique local/state laws, local and institutional considerations, and cultural backgrounds of the population from which research subjects will be drawn (e.g., ethnicity, educational level, religious affiliations, vulnerable populations, inter-community differences, etc.). Additional matters that require assessments include whether mechanisms of subject selection will be equitable, whether adequate provisions are made to minimize risks to vulnerable populations, and whether the informed consent process is adequate.2
Local IRB records should contain the agreements and procedures that the IRB and its host institution are required to follow to conduct clinical trials (according to 21 CFR 56.115(a)), including guidelines regarding initial and continuing review of clinical trials, reporting of protocol events, reporting of clinical trial findings, and other actions expected on the parts of the investigator and the institution.
Benefits of Using Local IRB
- Local IRBs can review multiple types of studies onsite, such as internally and externally funded trials.
- They can provide IRB services to other facilities and collaborating institutions as well.
- They can lead to a better understanding of local customs, sensitivity of community attitudes and ethical concerns, and standards of care in the community where the research study will be conducted and from which research participants will be drawn.
- The speed of the research protocol review is locally controlled.
- The IRB members and the investigators become familiar with each other and with the utilization of common research techniques, which is helpful in quick review of future upcoming studies.11
Issues with Using Local IRB
- In the U.S., local IRBs must be registered with the Office for Human Research Protections within the U.S. Department of Health and Human Services, which requires Federalwide Assurance.
- Start-up costs and annual expenditures of a local IRB can be considerable. The host institution pays the salaries of the IRB members and the staff associated with it.
- Additional financial burdens can or will emerge, tied to such matters as a) the requirement of having expert IRB members representing the therapeutic/research areas of focus at the institution, b) increases over time in study workloads leading to a need for more staff to accomplish the IRB requirements, c) development and maintenance of written IRB policies and procedures, and d) obtaining substantial institutional/facility support.
- The activities demanded of local IRBs can be time-consuming concerns, especially at institutions which are highly active research sites for both internally funded/investigator-initiated trials and externally funded trials.
Risks of Using Both Central and Local IRBs
Differences in what are considered approved research practices between multiple IRBs could affect the IRB review process and cause confusion for site staff. IRBs could interpret the same regulations differently as a whole, or interpretations among their individual members could differ. Therefore, in cases of complex protocols being reviewed, an IRB may want to apply higher (uniform) standards than those explained at a basic level in the federal regulations.6
For example, the expectations and criteria regarding staff reports of serious adverse events and protocol deviations could differ between local and central IRBs. As a result, some important events may not be reported. Research study staff are also burdened with multiple studies at one time; this could be an additional concern since the reporting criteria may differ between protocols as well as between IRBs.
The question arises, what are we going to achieve by using two IRBs for research study oversight? If the members of different IRBs are all qualified experts, it may be hoped that there is little to no variation in their opinions, assuming uniform regulatory standards are applied during the review process.
Monitoring is the most important and extensive part of clinical trials, as a study’s results rely on the accuracy of study data and the authenticity of clinical trial conduct. We do not duplicate the monitoring work, so why should we duplicate the IRB review process? Can we not achieve perfection without the redundancy? If not, then it would appear we need to duplicate every part of work in clinical trials, including coordinating, monitoring, PI review, FDA submission, etc.6
Benefits of Using Both Local and Central IRBs
Research study–related findings or violations that may go unnoticed in a review by one IRB may get caught by another IRB’s review, so having both a local and central IRB for study oversight can act as a double layer of protection for the study subjects and for ethical, quality conduct of clinical trials.
This article addressed various advantages and disadvantages of having central and institutional IRBs involved in the clinical trial process. The key responsibility of an IRB is to protect the rights, safety, and welfare of study subjects, which are essential matters in the clinical research process itself. We can achieve this goal by using either central or local IRBs, as long as the ethical practice of clinical trials are guaranteed and the autonomy and beneficence of study subjects are fully protected.
- National Cancer Institute. 2016. Central Institutional Review Board—Standard Operating Procedures. https://www.ncicirb.org/sites/ncicirb/files/CIRB%20SOPs%20051716_v2.pdf
- U.S. Department of Health and Human Services/Food and Drug Administration. Guidance for Industry—Using a Centralized IRB Review Process in Multicenter Clinical Trials. www.fda.gov/downloads/RegulatoryInformation/Guidances/ucm127013.pdf
- Marsden S, Melander M. Historical Cases of Unethical Research. https://www.und.edu/instruct/wstevens/PROPOSALCLASS/MARSDEN&MELANDER2.htm
- Federal Register (Vol. 46, p. 8966; January 27, 1981).
- Burman W, Breese P, Weis S, Bock N, Bernardo J, Vernon A. 2003. The Effects of local review on informed consent documents; from a multicenter clinical trials consortium. Contr Clin Trials 24:245–55. https://www.ncbi.nlm.nih.gov/pubmed/?term=The+Effects+of+local+review+on+informed+consent+documents%3B+from+a+multicenter+clinical+trials+consortium
- Silverman H, Hull SC, Sugarman J. 2001. Variability among institutional review boards’ decisions within the context of a multicenter trial. Crit Care Med 29(2):235–41. https://www.ncbi.nlm.nih.gov/pubmed/?term=Variability+among+institutional+review+boards%27+decisions+within+the+context+of+a+multicenter+trial
- McWilliams R, Hoover-Fong J, Hamosh A, Beck S, Beaty T, Cutting G. 2003. Problematic variation in local institutional review of a multicenter genetic epidemiology study. J Am Med Assoc 290(3):360–1. https://www.ncbi.nlm.nih.gov/pubmed/12865377
- Federal Register (Vol. 40, pp. 47688–700; August 14, 1979).
- Federal Register (Vol. 44, p. 47699; August 14, 1979) and Federal Register (Vol. 43, p. 56174; November 30, 1978).
- Federal Register (Vol. 46, pp. 8958–70; January 27, 1981).
- Rice TW. 2008. How to do human-subject research if you do not have an institutional review board. Resp Care 53(10):1362–7. www.rcjournal.com/contents/10.08/10.08.1362.pdf
Pranali M. Wandile, MS, CCRP, (email@example.com) is Site Director for Central Valley Research, LLC in Fresno, Calif.