Common FDA Bioresearch Monitoring (BIMO) Violations: Updates from FY 2023 to Now

The Bioresearch Monitoring (BIMO) Program, operated by the U.S. Food and Drug Administration (FDA), conducts on-site inspections and data audits in order to effectively monitor the compliance of all FDA-regulated research.

As a follow up to our July 2023 post, we highlight the most common violations identified in Fiscal Year (FY) 2023, in addition to those observed thus far in FY 2024.  BIMO conducted 1073 inspections in FY 2023.  The majority of these inspections (approximately 79%) were of drug, biologic, or medical device study clinical investigators, institutional review boards (IRBs), sponsors, clinical research organizations (CROs), and sponsor-investigators.  Some of the most common inspection outcomes are highlighted below. Our methodology included a search of FDA’s Warning Letter database for FY 2023 and 2024, to date, for letters issued by BIMO and the Center for Drug Evaluation and Research, the Center for Biologics Evaluation and Research, and the Center for Devices and Radiological Health to IRBs, CROs, clinical investigators, sponsors, and sponsor-investigators.

FY 2023:

BIMO conducted 681 inspections of clinical investigators (666 of which were assigned to FDA’s drug, biologic, and device Centers), making up well over half of BIMO’s inspections conducted in FY 2023.  Inspections of IRBs, sponsors, CROs, and sponsor-investigators assigned to FDA’s drug, biologic, and device Centers comprised another 169 inspections in FY 2023. Of the 681 clinical investigator inspections, only 9 resulted in a classification of “Official Action Indicated” (OAI) and 136 resulted in a classification of “Voluntary Action Indicated” (VAI). The most common inspection observations included: (1) failure to comply with Form FDA 1572 requirements and failure to follow the investigational plan; (2) inadequate and/or inaccurate case history records and inadequate study records; (3) inadequate subject protection and informed consent issues; (4) inadequate accountability and/or control of the investigational product; (5) and safety reporting and failure to report and/or record adverse events.

Of the Warning Letters that were issued in FY 2023 to clinical investigators, the most common observations were:

• Failure to ensure that the investigation was conducted according to the investigational plan. This finding in various Warning Letters included failure to properly administer the study drug, failure to properly randomize participants, and/or failure to properly screen potential participants to ensure they met a protocol’s inclusion and exclusion criteria prior to enrollment in an investigational plan. For example, in one Warning Letter, an investigator did not ensure that subjects received the study drug in the specific body locations indicated in the protocol.
• Failure to submit an IND application for the conduct of a clinical investigation with an investigational new drug. For example, the FDA noted that one clinical investigator failed to submit an IND for the use of a product that was determined by the FDA to be an investigational drug. Because the study compared the efficacy of marketed drugs and did not meet all of the IND exemption criteria for a lawfully marketed drug, the administration of the drugs was deemed to be a clinical investigation and not the practice of medicine.

BIMO conducted 103 inspections of sponsors and CROs in FY 2023 (99 of which were assigned to FDA’s drug, biologic, and device Centers). Of these, 0 resulted in a finding of OAI, though 16 were classified as VAI. The most common inspection observations included: (1) failure to ensure proper monitoring of the study and ensure the study is conducted in accordance with the protocol and/or investigational plan; (2) failure to meet the abbreviated requirements for investigational device exemptions (IDEs); (3) failure to maintain and/or retain adequate records in accordance with 21 CFR 312.57, including: accountability for the investigational product; Investigator Statement (Form FDA 1572); financial disclosures; (4) failure to submit an Investigational New Drug (IND) application and IND safety report; (5) failure to submit a current list of all participating investigators to FDA at six-month intervals after FDA approval of the study.

FY 2024 Trends (to date):

In 2024, we have already observed 6 Warning Letters issued to clinical investigators, sponsors, and IRBs, four involving failure to ensure that the investigation was conducted according to the investigational plan. Interestingly, to date in 2024, 4 of the 7 Warning Letters have related to IRB activities, including the IRB’s failure to ensure the informed consent form complied with Part 50, failure to ensure ongoing IRB review and approval of a study, failure to ensure IRB written procedures for prompt reporting of unanticipated problems to the IRB, and failure to ensure prospective IRB review of continued use of an investigational drug beyond two initial doses authorized for emergency access. For example, in a June 2024 Warning Letter, the FDA conducted a Remote Regulatory Assessment (RRA) of a prominent IRB and found that informed consent forms failed to: (1) include a disclosure of appropriate alternative procedures or courses of treatment, if any, that might be advantageous to the subject, as required by 21 C.F.R. § 50.25(a)(4); (2) for investigations involving more than minimal risk, include an explanation as to whether any compensation is available if injury occurs and, if so, what it consists of, or where further information may be obtained as required by 21 C.F.R. § 50.25(a)(6); and (3) include a statement that notes the possibility that the FDA may inspect the records, as required by 21 C.F.R. § 50.25(a)(5).

Last month, FDA issued Draft Guidance for Industry titled, Processes and Practices Applicable to Bioresearch Monitoring Inspections, which notes FDA’s RRAs and outlines BIMO’s processes and practices, including best practices for communications after an inspection that industry may find generally useful to consider for other types of FDA inspections as well. We discussed these in a recent blog post. At a June 2024 Society of Clinical Research Associates conference, the FDA also emphasized that written Form 483 inspection responses should employ the “5 Cs,” being clear, concise, compelling, complete, and compliant.

Finally, sponsors, clinical investigators, CROs, and IRBs should review the FDA’s BIMO Compliance Program Guidance Manuals regularly to ensure that they understand their responsibilities when carrying out clinical research involving human subjects. Sponsors, clinical investigators, CROs, and IRBs should ensure inspection readiness at all times while bioresearch is ongoing and following completion of bioresearch that may support marketing applications submitted to the FDA. Ensuring diligence in the research site selection process, careful monitoring during clinical trials, and corrective actions when deviations occur can help manage the risk of inspection findings of noncompliance or Warning Letters issued by the FDA. The Goodwin Life Sciences Regulatory & Compliance team provides regulatory counseling on FDA’s Good Clinical Practice requirements and the resolution of BIMO inspection findings and Warning Letters when they occur.

Josh Eibelman, a 2024 summer associate in Goodwin’s Boston office, contributed to this post.

This informational piece, which may be considered advertising under the ethical rules of certain jurisdictions, is provided on the understanding that it does not constitute the rendering of legal advice or other professional advice by Goodwin or its lawyers. Prior results do not guarantee a similar outcome.