Knock, Knock – FDA Issues Guidance on Best Processes and Practices During BIMO Inspections

Among FDA-regulated establishments and stakeholders, there is one word that makes everyone go on edge – the dreaded FDA “inspection.” In an effort to clarify for industry and alleviate some of the stress associated with these activities, last week the FDA issued a draft guidance aimed at providing recommendations on how to handle inspections under FDA’s Bioresearch Monitoring (BIMO) program. This draft guidance, titled “Processes and Practices Applicable to Bioresearch Monitoring Inspections,” was prompted by a congressional directive under the Food and Drug Omnibus Reform Act and is intended to provide recommendations that are not otherwise specified in existing publicly available guides and manuals for such inspections (see pgs. 11-12 of the guidance for a list of these resources).  It is critical that this guidance be reviewed in tandem with the guidance set forth in FDA’s Investigations Operations Manual (IOM) and the Regulatory Procedures Manual (RPM), both of which provide more detail about how FDA investigators conduct investigations and make decisions about a firm’s regulatory compliance.

As a reminder, the BIMO program oversees a wide range of activities related to FDA-regulated research, including human and animal studies, and covers the full gamut of FDA centers (CDER, CBER, CDRH, CFSAN, CTP, and CVM). BIMO inspections can consist of on-site inspections, data audits, and remote regulatory assessments of nonclinical laboratories, clinical investigators, sponsors, contract research organizations (CROs), bioequivalence facilities, institutional review boards (IRBs), and postmarketing surveillance. These inspections include unannounced or announced inspections conducted in support of FDA’s review of specific submissions or marketing applications or periodic establishment inspections and are conducted both domestically and internationally to monitor compliance with Good Laboratory Practice (GLP) and Good Clinical Practice (GCP).  In FY2023, FDA conducted over 1000 inspections under the BIMO program.

Below we highlight FDA’s views about best practices for BIMO inspection communications, handling requests for records, and inspection preparation and follow-up as outlined in the draft guidance.  We also detail some of our recommended best practices to achieve success when FDA comes knocking.

Pre-BIMO Inspection Communication Best Practices

• The FDA may provide a pre-announcement notice to ensure that the necessary records and personnel are available during the inspection and includes general information about what the FDA plans to review.
• Establishment staff should confirm arrival details with FDA investigators and provide a contact phone number. An establishment’s failure to acknowledge a pre-announcement notification is not a reason to delay the start of an inspection (see FDA’s revised draft guidance on Circumstances that Constitute Delaying, Denying, Limiting, or Refusing a Drug or Device Inspection).
• FDA investigators routinely share their names, titles, contact information, and, when appropriate, reasons for conducting the inspection. Establishment staff should take note of this information (either by writing it down or taking a picture of the investigator’s credentials).
• Establishments using electronic information systems to hold, analyze, process or transfer pertinent information should be prepared to provide FDA access to such systems.

Communication Best Practices During a BIMO Inspection

• Provide timely and accurate responses to information requests.
• Ask clarifying questions.
• Discussions between FDA investigators/personnel and establishment staff should include observation clarifications.

Post-BIMO Inspection Communication Best Practices

• Discuss inspection findings during an inspection close-out meeting. During this meeting, the FDA investigator will notify the establishment whether a Form FDA 483 will be issued with observations of objectionable conditions and practices identified during the inspection.
• If the FDA issues a Form FDA 483, the FDA “encourages” responses within 15 business days of the close-out of the inspection. Importantly, FDA notes in the draft guidance that any responses received within this window “will be considered before further Agency action or decision.”
• An establishment’s response to a Form FDA 483 should, in addition to being submitted within 15 business days of the close-out of the inspection:
  • Demonstrate the establishment’s acknowledgement and understanding of FDA’s observations and the establishment’s commitment (including from senior leadership) to address such observations.
  • Address each observation separately.
  • Note whether the establishment agree(s) or disagree(s), and why.
  • Provide both corrective and preventive actions (CAPAs) and timelines for completion.
  • Provide both completed and planned actions and related timelines.
  • Provide a method of verifying or monitoring the effectiveness of the actions.
  • Submit documentation as evidence of addressing the observations (e.g., training, standard operating procedure (SOPs), corrective action plans, records, etc.).
• Develop and implement corrective and preventive action plans to resolve issues.
• Document all corrective actions and follow-up to ensure sustained compliance.
• If an establishment has any questions about the FDA investigator, the establishment may request the contact information for the Office of Bioresearch Monitoring Operations (OBIMO) division management from the FDA investigator during the close-out meeting.
• If an inspected establishment has any questions about the inspection classification itself, such questions can be directed to the FDA center point-of-contact identified in the post-inspection correspondence or in the relevant compliance program.
• Unresolved concerns relating to an inspection can be directed to the ORA Ombudsman Program.

Other Inspection Best Practices

• Develop a clear SOP for inspections, including the roles and responsibilities of staff.
• Ensure all relevant records and data (whether electronic or otherwise) are readily accessible and organized for review. Delays in producing records without reasonable explanation may cause drugs or devices to be adulterated under the Food, Drug, and Cosmetic Act (see FDA’s revised draft guidance on Circumstances that Constitute Delaying, Denying, Limiting, or Refusing a Drug or Device Inspection).
• Foster open and transparent communication with FDA investigators and engage in proactive communication to clarify any potential issues or misunderstandings.
• Regularly review and update SOPs to reflect current regulatory requirements.
• Conduct internal audits to identify and address compliance issues before inspections.

• Maintain accurate and detailed records of all research activities, including raw data, test results, and correspondence.
• Ensure records are securely stored and protected from unauthorized access or tampering.
• Implement a robust data management system to track and retrieve records efficiently.
• Provide ongoing training for staff on regulatory requirements and inspection processes.
• Ensure staff are knowledgeable about their roles and responsibilities during inspections.
• Promote a culture of compliance and quality within the organization.

Comments on the draft guidance can be submitted to the docket by August 5, 2024.