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This article will focus on specific requirements to ensure the Protection of Human Research Subjects (Title 45 CFR 46).
FWA, FDA, CFR, IRB! The list of acronyms corresponding to the various entities and requirements needed to conduct a clinical study is never ending. In the world of clinical research and site management, knowing all the regulatory requirements is a task by itself, especially as it relates to the ambiguous issue of “Ethics.” However, as a result of various historical, unethical research events that occurred in the United States and internationally, the importance of understanding ethical standards, policies, and regulations as well as the entities that ensure compliance is key to the success of your research study. In particular, this paper will focus on specific requirements to ensure the Protection of Human Research Subjects (Title 45 CFR 46).
In June 2000, the Office of Human Research Protection (OHRP) was re-established (as it was formally known as the Office for Protection from Research Risk) to provide leadership in the protection of the rights, welfare, and well-being of subjects involved in research conducted or supported by the US Department of Health and Human Services (HHS) and ensure compliance with Title 45 CFR 46. As part of their oversight responsibilities, OHRP evaluates all written substantive allegations or indications of noncompliance with the HHS regulations. Therefore, an institution (domestically and internationally) engaged in non-exempt human subject’s research conducted or supported by federal funds must submit to OHRP written assurance that it will comply with the HHS regulations, known as a Federal Wide Assurance (FWA). In addition to the requirement for a FWA, OHRP requires that all human subjects research must be reviewed by an Institutional Review Board (IRB) with knowledge of the local research context. As a result, OHRP maintains a list of all sites under an FWA, IRB organizations and individual IRB registrations. The following information should provide an insight into the purpose and requirements of each entity as well as illustrate how they relate to each other.
The IRB Organization (IORG) is the institution or organization affiliated with an IRB or a group of IRBs. The IORG number is a unique number assigned by the OHRP to an institution or organization the first time the institution or organization is registered to an IRB. IRBs are operated by IORGs, and each IORG can register one or more IRBs.3 IORGs registration lasts for three years.4 Therefore, a renewal is required prior to the date of expiration.
The OHRP website can be used to search for an IORG. Once the IORG is identified and selected, it will indicate all IRBs associated with that IORG and there is a column labeled “IRB Type.” The IRB Type listed for each IRB indicates the classification of studies that the IRB has indicated it will be reviewing: “FDA” for United States FDA regulated studies (IND or IDE studies) and/or “OHRP” for other studies (such as non-IND).3 It is important to ensure that the approving IRB for a study has the appropriate IRB Type listed for the classification of the study it will be approving. In addition, the IORG must be listed as active with a future expiration date in order for it to be linked to a valid IRB who can approve a study that is federally funded.
Federal Wide Assurance (FWA)
An institution/organization must have an FWA in place when receiving federal support or funding for research involving human subjects. The institution must commit to HHS that it will comply with the requirements as seen in the HHS Protection of Human Subjects regulations (45CFR Part 46)1, and which applies to both domestic and international institutions. Failure to comply with the assurance can result in the suspension or restriction of an institution’s research. An institution’s FWA must be renewed every five years.1
The FWA listing on the OHRP website will include all names and locations for an institution, the expiration date and IRBs linked to the assurance. The site study files should include documentation from the OHRP or printed from the OHRP website that the institutions FWA is active with the correct location, site name, and future expiration date. Although an IRB is often linked to an FWA, below describes instances where IRBs may be used by an institution but not linked to the site’s FWA.
Institutional Review Boards (IRB)
According to 21 CFR 56.106, all IRBs based in the US that review FDA-regulated studies are required to register with OHRP. However, any IRB, including non-US IRBs that review FDA-regulated studies, may choose to register voluntarily.2 When an IRB registers with OHRP it agrees to comply with 45 CFR Part 46, which includes requirements to have annual documented IRB reviews of each study. In addition, the IRB must be comprised of at least five members, cannot be entirely made of men or women, at least one non-scientific and scientific member, at least one member who is not affiliated (or related to an employee) of the institution, and none of the members can be study staff for the study being approved.3 An IRB must renew its OHRP registration every three years.3
The IRB information on the OHRP website includes the name of the registered IRB, location, date membership was last updated as well as the IRB expiration date and all assurances that rely on that IRB. If the IRB is located within the institution, it may be listed as an IRB within the FWA number. If an external IRB is used for review, this IRB may not be listed within the FWA component of the OHRP website.1 If an Institution chose to use an external IRB, they must ensure that this arrangement is documented by a written agreement (Reliance Agreement) between the institution and the other institution or organization operating the IRB that outlines their relationship. When confirming the status of the IRB on the OHRP website, it is important to ensure that the IRB is listed as “Active” and has a future expiration date. This shows it is current with its registration to OHRP.
As depicted in the above chart, the linking of the various entities provides a solid backbone for the protection of human subjects enrolled in research programs/protocols. Without the existence of the various entities and requirements mentioned above, there will not be any safeguards in place for the protection of subjects involved in research.
Take home messages:
1. If you have a U.S. federally funded study, make sure all participating institutions are registered with OHRP.
2. Under the IORG information, ensure the appropriate IRB type that covers your study is listed and the IORG is active.
3. Under the FWA information, ensure the status is listed as active and note the expiration date.
4. Under the IRB registration information, ensure the IRB of record is consistent with an active registration and note the expiration date.
Emelia Annum, MS, CCRP, Clinical Research Associate II, Roxanne Cox, MA, Clinical Project Manager I, Lisa Hoopengardner, M.S., CCRA, Clinical Trials Manager I and Shelly M. Simpson, M.S. Clinical Trials Director are all with the Clinical Trials Management/Clinical Monitoring Research Program Directorate, Frederick National Laboratory for Cancer Research sponsored by the National Cancer Institute, https://frederick.cancer.gov/science/clinical/clinical-monitoring-research-program; Susan E. Vogel, Clinical Research Oversight Manager, and Jerome F. Pierson, PhD, Director are both with the Office of Clinical Research Policy and Regulatory Operations/Division of Clinical Research/National Institute of Allergy and Infectious Diseases, https://www.niaid.nih.gov; and Elizabeth Baseler, MS, Director, Clinical Monitoring Research Program Directorate, Frederick National Laboratory for Cancer Research sponsored by the National Cancer Institute, https://frederick.cancer.gov/science/clinical/clinical-monitoring-research-program
1Assurance Process Frequently Asked Questions (FAQs). (2017, May 10). Retrieved from https://www.hhs.gov/ohrp/register-irbs-and-obtain-fwas/fwas/assurance-process-faq/index.html
2Guidance for Institutional Review Boards (IRBs) Frequently Asked Questions – IRB Registration. (2009, July). Retrieved from https://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM171256.pdf
3IRB Registration Process Frequently Asked Questions (FAQs). (2017, May 10). Retrieved from https://www.hhs.gov/ohrp/register-irbs-and-obtain-fwas/irb-registration/irb-registration-faq/index.html
4Update and Renewal of an IORG-IRB Registration (2009, July 9). Retrieved from https://archive.hhs.gov/ohrp/humansubjects/assurance/renwirb.htm
This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.