Clinical research involving human participants is critical
to develop treatments for a broad spectrum of diseases,
including many endocrine disorders lacking specialized
treatments. To conduct research with human participants,
clinical investigators must apply for approval by Institutional
Review Boards (IRBs) which ensure that human subjects
research is conducted in accordance with applicable ethical
and legal guidelines. When a study utilizes facilities spanning
multiple institutions, each institution’s individual IRB typically
reviews and approves the research proposal, unless a
single IRB of record, referred to herein as a Federated IRB
(FIRB) is employed. When multiple, local IRBs are used, the
inherent variability in the requirements and review processes
among institutions frequently results in a large increase in
application processing time and delays in protocol approval,
hindering overall progress of the study. In addition, individual
IRBs may request different and sometimes conflicting
changes to study design, necessitating re-review by other
IRBs. There is evidence that multiple independent reviews
do not promote superior participant safety nor higher
ethical standards for clinical research.1 To streamline the
IRB approval process, improve consistency, and assure
accountability, the US National Institutes of Health (NIH) and
other federal agencies have proposed policies and guidelines
to support the use of FIRBs for multicenter clinical studies.
Approval or explicit exemption by the IRB is required
of all clinical studies involving human participants. IRB
review is meant to evaluate the ethical implications of
the proposed research and to promote the welfare of all
study participants. A significant portion of IRB guidelines
involves oversight of the process of informed consent
of prospective research participants and emphasizes
full disclosure of information to the potential participant.
The IRB considers safety and efficacy of test agents and
interventions as well as the scientific merit of the project.
Flagrant human rights abuses in the mid-20th century
highlighted the need for IRBs due to the lack of appropriate
protections for human participants in research. In several
high-profile cases, patients were unethically subjected
to serious experimental risks without informed consent.
These patients experienced severe harms, and even
death, as a result of participating in clinical research.2
Infamous examples like the Tuskegee Study of Untreated
Syphilis prompted the National Research Act of 1974.
In the US, IRBs are now governed by Title 45 of the
Code of Federal Regulations (http://ohsr.od.nih.gov/
guidelines/45cfr46.html), with explicit intent to protect the
rights of research participants and to provide full disclosure
of medical information related to study participation.
Individual institutions are responsible for maintaining IRBs
that uphold national, state, and local laws, along with
institutional policies regarding the safety of human research
participants. Commercial, for-profit FIRBs independent
of specific institutions have recently gained traction to
protect study participants with increased efficiency and
consistency across institutions. Often called “Central
IRBs”, these FIRBs typically conduct both the initial and
continuing review of applications and in some cases, FIRBs
work in conjunction with individual local IRBs to ensure
conformity with local requirements. In other cases, the local
IRB cedes authority to the FIRB by written agreement.
Recognizing that the use of FIRBs can reduce administrative
burdens while maintaining or even enhancing protections
for research subjects in multi-center studies, the NIH
proposed a draft policy to promote the use of a single
IRB of record for domestic sites of multi-center studies
funded by the NIH.3 In 2015, the US Department of Health
and Human Services (DHHS) proposed updates to the
Common Rule, a set of ethical rules that apply broadly to
Federal Agencies conducting human subjects research.4
Included in the update is the requirement to use a single
IRB of record for most multi-center research studies.
The IRB review process, which was initially set up to
protect research participants, has in some cases become
increasingly sidetracked by local bias, conflict of interest,5
and increasing institutional demands that distract IRBs
from their primary purpose. Instances of non-compliance
by individual investigators, along with some high-profile
episodes of IRB ineffectiveness6,7 have led to institutional
concerns about liability and decreased focus on the basic
elements of IRB review. Many institutions have reacted
to these concerns with a proliferation of paperwork
required from the IRB to document compliance.
The number of IRB approvals necessary to proceed with
a multi-site study that utilizes each site’s IRB may delay
enrollment by a year or more, as each institution reviews
the application and has a separate dialogue with each site’s
principal investigator. Furthermore, while it is not the purpose
of IRBs to review the scientific approach of the proposed
research per se, it is not uncommon for IRBs to undertake
some level of scientific review,8 further delaying the time
to approval. Most studies evaluated by IRBs have been
previously deemed to be sound by peer review. Though
it is appropriate and ethical for an IRB to object to poorly
conceived scientific premises, it is unnecessarily cumbersome
and duplicative for an IRB to engage in extensive review
of the minutiae of a protocol, especially if the proposal has
already undergone rigorous peer review. Moreover, different
IRBs at different institutions may approve or disapprove
portions of the same research project according to their
own internal guidelines, completely halting progress and/
or introducing inconsistencies into protocol implementation.
These variations reduce the scientific value of the study and
create unintentional flaws in the study design. This process
delays study progress, discourages the investigator(s),
and introduces inefficiencies and inconsistencies
that reduce the cost effectiveness of research.9
Previous announcements by federal agencies — including
the Food and Drug Administration, Office of Human Research
Protections, and the NIH — have strongly supported the use
of FIRBs for multi-center studies. Widespread adoption of
FIRBs in the US has not yet been achieved due to concerns
about regulatory or legal liability and other perceived
barriers.10 The Endocrine Society is therefore encouraged
by the new NIH and DHHS proposals to require the use
of FIRBs for multi-site research. A single Federated (or central) IRB of record can address major institutional about
liability, risk, and conflict-of interest and may better facilitate
the progress of multicenter clinical research studies.
It will be critical to ensure that new policies to mandate
FIRBs are implemented effectively and with limited disruption
to new or ongoing clinical studies. Legal requirements
may differ between local, national, and international sites
of large clinical trials. Appropriate guidance will therefore
be needed to ensure that FIRBs are able to appropriately
apply local laws, or effectively and efficiently delegate
responsibility to local IRBs when necessary. Several
successful FIRBs are already in place, including FIRBs
facilitated by the Veterans Administration, National Cancer
Institute, and independent committees such as the
Western, Independent, and Sterling IRBs. Furthermore,
international models exist for centralized review of ethical
issues surrounding human subjects research. These and
other models for FIRBs could serve as case studies for
institutions and agencies as they implement policies to
support the use of single IRBs for multi-center studies.11
The Endocrine Society views patient safety as a top priority to
implement both good research practice and clinical practice.
The Endocrine Society supports NIH and DHHS efforts to
promote the utilization of federated IRBs for multi-center
clinical studies in order to advance clinical research
and improve patient care while maintaining the highest
safety standards for research participants. However,
additional steps must be taken by institutions, investigators,
and federal agencies to facilitate the use of FIRBs. The
Endocrine Society supports the following positions:
The Association for the Accreditation of Human
Research Protection Programs (AAHRPP) or a
similar entity should enforce a certification process
to ensure the quality and compliance of FIRBs.
Building on the model established by the National Cancer
Institute Central IRB,12 NIH and other sponsors of human
subject research should establish and fund institute
or agency specific FIRBs for all multi-center trials.
Federal agencies should issue detailed and
explicit guidance that recognizes the different
models for FIRBs, clarifies institutional liability,
and alleviates accountability concerns.
Institutions and agencies should conduct research
to compare the effectiveness of different FIRB
models for various multi-center studies in the
US and worldwide. Revised guidance should
disseminate and encourage best practices.
Researchers, institutions, and professional societies
should work to develop effective international
practices and models that facilitate the use of
FIRBs for international multi-center studies.
Revised April 2016
Menikoff, J. The paradoxical problem with multiple-IRB
reviews. New Engl J Med 2010;363:1591-1593.
Kim, WO. Institutional review board (IRB) and ethical issues in clinical
research. Korean J Anesthesiol. 2012;62:3–12.
NOT-OD-15-026: Request for Comments on the Draft NIH Policy on the Use of a
Single Institutional Review Board for Multi-Site Research. http://grants.nih.gov/grants/
guide/notice-files/NOT-OD-15-026.html. Accessed October 14, 2015.
http://www.hhs.gov/news/press/2015pres/09/20150902b.html. Accessed October 14, 2015.
McNeil, C. Central IRBs: why are some institutions reluctant to
sign on? J Natl Cancer Inst 2005;97:953-955.
Stolberg, Sheryl Gay. The biotech death of Jesse Gelsinger. The New York Times; November 28, 1999.
Bor, Jonathan and Cohn, G. Research volunteer dies in Hopkins
asthma study. The Baltimore Sun; June 14, 2001.
Gunsalus, CK et al. Mission creep in the IRB world. Science 2006;312:1441.
Kano, M et al. Costs and inconsistencies in US IRB review of low-risk
medical education research. Med Educ 2015;49:634-637.
Flynn KE, et al. Using central IRBs for multicenter clinical trials in
the United States. PLoS ONE 2013;8:e54999.
Check, DK et al. Use of central institutional review boards for multicenter clinical trials
in the United States: a review of the literature. Clinical Trials 2013;10:560-7.