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Registration is required for FDA-regulated IND studies, but is it needed for non-IND studies?
This article seeks to inform sponsors preparing for study start-up and enrollment by providing a brief review of the requirements of 21 CFR 56.106. While institutional review board (IRB) registration with Office for Human Research Protections (OHRP) has been a requirement for federally-funded projects since 2000 under the Federal Wide Assurance (FWA) system, registration of US investigational new drug (IND) studies has only been required since 2009, and remains voluntary for non-IND studies. Some sponsors, intending to rely on non-IND, non-US studies to support NDAs, are actively encouraging non-US Ethics Committees to complete this registration step.
In practical terms, depending on company or CRO set-up and size, the regulatory affairs, clinical operations, or clinical compliance group responsible for reviewing "the regulatory packet" routinely verify that the IRB named on the form FDA 1572 is registered and, based on their internal guidances and SOPs, may preclude drug shipment to these sites until they have documentation that the IRB is registered. While this is an appropriate step, it should be noted that registration of an IRB does not provide any guarantees of the accuracy of the registered information, or represent accreditation of that IRB.
For non-US ethics committees, there seems to be less consistency across sponsors, since IRB registration is voluntary. Given the Office of the Inspector General's (OIG) previously expressed concern about the ability of sponsors to assure an equivalent level of human protection in clinical studies of FDA-regulated products conducted outside of the United States,1 the considerable FDA, sponsor, and investigational site resources required to coordinate an overseas regulatory agency inspection, and the trend towards generation of clinical data outside the United States, some sponsors are choosing to drive for a harmonized approach in the absence of an absolute regulatory requirement, in an effort to prevent costly delays or temporary confusion at the final NDA approval stage.
The purpose of the regulation is to identify more precisely those IRBs reviewing clinical investigations regulated by FDA and to generate a comprehensive listing of all US IRBs. The preamble to the final rule that instituted these registration requirements for IRBs,1 and the accompanying Frequently Asked Questions document2 provide valuable insights on the agency's intent.
Drivers for the updated regulation included two reports from OIG, (one in 19983 and a follow up report in September 20074) which noted that FDA could not properly organize, schedule, or prioritize its onsite bioresearch monitoring (BIMO) inspection program because it did not maintain an IRB registry and did not have a complete list of IRBs. A secondary use of the registration system is dissemination of information to IRBs from FDA, thus facilitating outreach and educational efforts and assuring that IRBs receive information about current FDA policies. There may be considerable benefits to receipt of this information by overseas ethics committees who seek to understand FDA's viewpoint and fully prepare for a possible future inspection.
Prior to issuance of the final rule, much of FDA's knowledge about the identities and numbers of IRBs reviewing clinical investigations was based on information submitted by sponsors or investigators involved in clinical investigations regulated under an IND or Investigational Device Exemption (IDE). The reporting requirements were not harmonized across the different types of products regulated by FDA (e.g., human drug products, investigational devices, food additive studies involving human subjects), nor was the format of required information organized in such a way to facilitate its compilation for use by FDA's clinical research inspectorate, BIMO. For example, IRB names and addresses submitted to the IND include multiple copies of the form FDA 1572 for each center, as generated throughout study conduct, and the final clinical study report prepared according to ICH guideline E3.5 There was considerable potential for BIMO to select outdated or incomplete information garnered from these indirect sources and for this to have a detrimental effect on the use of limited inspection resources.
The final rule that added section 56.106 to Title 21 of the Code of Federal Regulations was published in the Federal Register on January 19, 2009, with an effective date of July 14, 2009 and a requirement for IRBs to register, or update their existing registrations to achieve compliance with the new rule, by September 14, 2009. This regulatory action was preceded by publication of a proposed rule on July 6, 20046 and receipt of comments from individuals; IRB members; IRB associations; an IRB accreditation association; government, health, academic or trade associations; a university system; and drug companies. In general, the comments supported IRB registration. Table 1 presents a summary of the key aspects of the IRB registration requirements and the clarifications provided in the preamble to the final rule or the frequently asked questions issued in July 2009. This summary demonstrates that the requirements are not especially onerous for a properly constituted IRB or ethics committee and thus may provide encouragement to those overseas entities not currently engaged in reviewing IND or IDE studies to consider proactive registration. Additionally, for those US studies that may or may not need to be conducted under an IND,8 assuring that IRB registration is in place removes a potential rate-limiting step to study start up.
Table 1. A quick look at the rules and requirements of IRB registration.
Alison Bowers,* MSc, RAC, FTOPRA, Senior Consultant at Parexel Consulting, 4600 East West Highway, Suite 350, Bethesda, MD, e-mail: Alison.Bowers@parexel.com. Anita Woodring, MS, RAC, Regulatory Project Leader at RTI International.
*To whom all correspondence should be addressed.
1. Food and Drug Administration, HHS, final rule, "Institutional Review Boards; Registration Requirements," Federal Register 74 (10) 2358-2369 (January 15, 2009), http://www.fda.gov/OHRMS/DOCKETS/98fr/E9-682.htm.
2. Food and Drug Administration, Guidance for Institutional Review Boards (IRBs) "Frequently Asked Questions—IRB Registration," (FDA, Rockville, MD, 2009), http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM171256.pdf.
3. Department of Health and Human Services, Office of the Inspector General, "Institutional Review Boards: A Time for Reform," (June 8, 1998), http://oig.hhs.gov/oei/reports/oei-01-97-00193.pdf.
4. Department of Health and Human Services, Office of the Inspector General, "The Food and Drug Administration's Oversight of Clinical Trials," (September 2007), http://oig.hhs.gov/oei/reports/oei-01-06-00160.pdf.
5. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, "Structure and Content of Clinical Study Reports: E3," (November 30 1995), http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E3/Step4/E3_Guideline.pdf.
6. Food and Drug Administration, HHS, proposed rule, "Institutional Review Boards; Registration Requirements" Federal Register 69 (128), 40556-40562 (July 6, 2004).
7. The Association for the Accreditation of Human Research Protection Programs, "The Benefits of Accreditation," http://www.aahrpp.org/www.aspx?PageID=12.
8. Food and Drug Administration, "Draft Guidance for Industry: Investigational New Drug Applications (INDs) - Determining Whether Human Research Studies Can Be Conducted Without an IND," (FDA, Rockville, MD, 2010), http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM229175.pdf.